Indole and indoline derivatives and methods of use thereof

ABSTRACT

The present application relates to indole and indoline derivatives of formula (I), (II), (III), (IV), (V), or (VI) 
                         
wherein a, R 1 , R 2 , R 3 , R 4 , R 5 , U, V, W, X, Y, and Z are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating disease conditions using such compounds and compositions, and methods for identifying such compounds.

This patent application claims priority to U.S. Provisional PatentApplication No. 61/101,054, filed Sep. 29, 2008, and U.S. ProvisionalPatent Application No. 61/225,452, filed Jul. 14, 2009, the entirety ofeach application is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to indole and indoline derivatives,compositions comprising these indole and indoline derivatives, methodsof preventing or treating disease conditions such as neurodegenerationor neuropsychiatric disorders using such compounds and compositions, andprocesses for preparing such compounds and compositions.

BACKGROUND OF THE INVENTION

Treatment of dementias of various types, such as but not limited to,Alzheimer's disease (AD), Parkinson's disease, Huntington's disease andother forms, continue to be unmet medical needs. Alzheimer's disease isthe most common form of dementia, wherein loss of memory and otherintellectual abilities are serious enough to interfere with dailyliving. Alzheimer's disease is an age-related neurodegenerative disordercharacterized by progressive loss of memory accompanied with cholinergicneurodegeneration (Kar, S.; Quirion, R. Amyloid β peptides and centralcholinergic neurons: functional interrelationship and relevance toAlzheimer's disease pathology. Prog. Brain Res. 2004, 145 (Acetylcholinein the Cerebral Cortex), 261-274.). This disease accounts for over 50%of all progressive cognitive impairment in elderly patients. Theprevalence increases with age. Alzheimer's disease is classified by itsseverity as mild, moderate and severe. The pathological hallmarks of ADinclude neuronal dysfunction/death, accumulation of senile plaquesextracellularly and neurofibrillary tangles (NFTs) intraneuronally.Several hypotheses have been put forth to explain the pathophysiology ofthis disease, including aberrant β-amyloid (Aβ) metabolism,hyperphosphorylation of cytoskeletal proteins, genetic predispositionsuch as mutations in genes coding for presenilin-1 and -2 (PS-1 andPS-2) and amyloid precursor protein (APP), apolipoprotein E genotype,oxidative stress, excitotoxicity, inflammation and abnormal cell cyclere-entry. However to date, none of these hypotheses is sufficient toexplain the diversity of biochemical and pathological abnormalities inAD.

Two pathological hallmarks of AD are generally recognized: senileplaques composed of β-amyloid peptide 1-42 (Aβ₁₋₄₂) and neurofibrillarytangles (NFTs) formed by abnormal polymerization ofmicrotubule-associated protein tau (Walsh, D. M.; Selkoe, D. J.Deciphering the molecular basis of memory failure in Alzheimer'sdisease. Neuron 2004, 44(1), 181-193.). While the precise causeunderlying AD-related memory loss and cognitive changes remains to befully elucidated, there is evidence indicating that pathologicalassemblies of Aβ₁₋₄₂ cause diverse forms of AD and that tau plays a roleincluding in mechanisms leading to Aβ₁₋₄₂-induced neurodegeneration.More recent evidence from studies using transgenic animals suggests thattau pathology exacerbates neurodegenerative and cognitive processes inthe presence of Aβ₁₋₄₂ (Oddo, S.; Caccamo, A.; et al. Temporal Profileof Amyloid-β (Aβ) Oligomerization in an in Vivo Model of AlzheimerDisease: a link between Aβ and tau pathology. J. Biol. Chem. 2006,281(3), 1599-1604.). In addition to Aβ and tau, dysregulation of calciumhomeostasis also plays an integral role in the pathophysiology of AD(Green, K. N.; LaFerla, F. M. Linking calcium to Aβ and Alzheimer'sdisease. Neuron 2008, 59(2), 190-194.). It is becoming evident thatdysregulation of mitochondrial function and resultant altered cellularhomeostasis increasingly contributes to the pathology ofneurodegenerative diseases such as AD (Moreira, P. I.; Santos, M. S.; etal. Is mitochondrial impairment a common link between Alzheimer'sdisease and diabetes? A matter under discussion. Trends Alzheimer's Dis.Res. 2006, 259-279. Beal, M. F. Mitochondria and neurodegeneration.Novartis Found. Symp. 2007, 287 (Mitochondrial Biology), 183-196. Reddy,P. H.; Beal, M. F. Amyloid beta, mitochondrial dysfunction and synapticdamage: implications for cognitive decline in aging and Alzheimer'sdisease. Trends Mol. Med. 2008, 14(2), 45-53.).

Mitochondria play major roles in bioenergetics and cell death/survivalsignaling of the mammalian cell as they are ‘gatekeepers of life anddeath’. Mitochondrial dysfunction contributes to the pathogenesis ofvarious neurodegenerative diseases with pathophysiological consequencesat multiple levels including at the level of calcium-drivenexcitotoxicity. One of the primary mitochondrial mechanisms is themitochondrial permeability transition pores (MPTP) that represent amultiprotein complex derived from components of inner and outermitochondrial membrane. The pores regulate transport of ions andpeptides in and out of mitochondria, and their regulation is associatedwith mechanisms for maintaining cellular calcium homeostasis. A deficitin mitochondria is the earliest feature of neurodegenerative diseases.One general characteristic of aging and neurodegeneration is an increasein the number of neuronal cells undergoing signs of apoptoticdegeneration. A key role for this apoptotic process is attributable tothe mitochondrial permeability transition pore, which provides transportin and out of mitochondria for both calcium ions and compounds with lowmolecular weight. It has been proposed that MPTP is a multiproteincomplex with the outer membrane fragment including porin (avoltage-dependent ion channel), anti-apoptotic proteins of the Bcl-2family, and the peripheral benzodiazepine receptor. The inner fragmentof MPTP contains an adenine nucleotide translocator and cyclophilin,which may interact with proapoptotic proteins of the Bax family.Inhibition of mitochondrial calcium uptake and/or blocking of MPTP mayprotect cells against the development of apoptosis in the presence ofpathological factors such as excitotoxins and anti-oxidants. Indirectmodulation of MPTP via kinase pathways is also known wherein glycogensynthase kinase-3β (GSK3β) mediates convergence of protection signalingto inhibit the mitochondrial MPTP (Juhaszova, M.; Zorov, D. B.; et al.Glycogen synthase kinase-3β mediates convergence of protection signalingto inhibit the mitochondrial permeability transition pore. J. Clin.Invest. 2004, 113(11), 1535-1549. Juhaszova, M.; Wang, S.; et al. Theidentity and regulation of the mitochondrial permeability transitionpore: where the known meets the unknown. Ann. N. Y. Acad. Sci. 2008,1123 (Control and Regulation of Transport Phenomena in the CardiacSystem), 197-212) and mitochondrial localization during apoptosis(Linseman, D. A.; Butts, B. D.; et al. Glycogen synthase kinase-3βphosphorylates Bax and promotes its mitochondrial localization duringneuronal apoptosis. J. Neurosci. 2004, 24(44), 9993-10002.).Furthermore, calcium-dependent activation of MPTP in brain mitochondriaenhances with age and may play an important role in age relatedneurodegenerative disorders.

Neuroprotective effects of agents have been linked to various cellularprocesses including inhibition of mitochondrial MPTPs. For example, theneuroprotective effects of 4-azasteroids parallel the inhibition of themitochondrial transition pore (Soskic, V.; Klemm, M.; et al. Aconnection between the mitochondrial permeability transition pore,autophagy, and cerebral amyloidogenesis. J. Proteome Res. 2008, 7(6):2262-2269.). In vivo administration of MPTP inhibitor,1-(3-chlorophenyl)-3-phenyl-pyrrole-2,5-dione to a mouse model ofmultiple sclerosis significantly prevented the development of thedisease (Pelicci, P., Giorgio, M.; et al. MPTP inhibitors for blockadeof degenerative tissue damages. WO 2008067863A2). Compounds such asdimebolin (latrepirdine,2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-1H-pyrido[4,3-b]indole)have been shown to improve neuronal function and a role for improvedneuronal outgrowth and mitochondrial function has been suggested.Dimebolin has been shown to inhibit neuronal death in models of AD andHuntington's disease, another neurodegenerative disease (Lermontova, N.N.; Lukoyanov, N. V.; et al. Dimebone improves learning in animals withexperimental Alzheimer's disease. Bull. Exp. Biol. Med. 2000, 129(6),544-546. Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebonas a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad.Sci. 2001, 939 (Neuroprotective Agents), 425-435.). More recently,dimebolin has been shown to possess a clinically beneficial effect incognition in patients with AD (Burns, A.; Jacoby, R. Dimebon inAlzheimer's disease: old drug for new indication. Lancet 2008,372(9634), 179-80. Doody, R. S.; Gavrilova, S. I.; et al. Effect ofdimebon on cognition, activities of daily living, behaviour, and globalfunction in patients with mild-to-moderate Alzheimer's disease: arandomised, double-blind, placebo-controlled study. Lancet 2008,372(9634), 207-215.). Patients with mild-to-moderate Alzheimer's diseaseadministered with 20 mg three times a day (60 mg/day) showed significantimprovement in the clinical course of disease, as reflected inimprovement over baseline for ADAS-Cog (Alzheimer's disease assessmentscale—cognitive subscale). In particular, dimebolin-treated patientsdemonstrated a significant improvement over placebo in cognition, globalfunction, activities of daily living and behavior. A six-monthopen-label extension trial of dimebolin produced results similar tothose in the preceding 12-month clinical trial (Cummings, J.; Doody, R.;Gavrilova, S.; Sano, M.; Aisen, P.; Seely, L.; Hung, D. 18-month datafrom an open-label extension of a one-year controlled trial of dimebonin patients with mild-to-moderate Alzheimer's disease. Presented at theInternational Conference on Alzheimer's Disease (ICAD), Chicago, Ill.,USA, July 2008; paper P4-334.). Patients with mild-to-moderate AD whohad earlier received the drug for 12 months had preservation of functionclose to their starting baseline on key symptoms of AD. Patientsoriginally on placebo who received dimebolin in the extension studyshowed stabilization across all key measures.

Dimebolin has been approved in Russia as a non-selective antihistamine.The drug was sold for many years before selective anti-histaminergicagents were developed. Although dimebolin was initially thought to exertits cognitive enhancing effects through inhibition ofbutyryl-cholinesterase, acetyl cholinesterase, NMDA receptor or L-typecalcium channels (Bachurin, S.; Bukatina, E.; et al. Antihistamine agentdimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y.Acad. Sci. 2001, 939 (Neuroprotective Agents), 425-435. Lermontova, N.N.; Redkozubov, A. E.; et al. Dimebon and tacrine inhibit neurotoxicaction of beta-amyloid in culture and block L-type Ca(2+) channels.Bull. Exp. Biol. Med. 2001, 132(5), 1079-1083. Grigor'ev, V. V.; Dranyi,O. A.; et al. Comparative Study of Action Mechanisms of Dimebon andMemantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat CerebralNeurons. Bull. Exp. Biol. Med. 2003, 136(5): 474-477), its interactionsat these targets are weak. More recent data suggest that dimebolin mayexert its effects at the level of mitochondria, and that theseactivities could enhance neuronal function (Hung, D. Dimebon: A phase 3investigational agent for Alzheimer's disease with a novel mitochondrialmechanism of action. Presented at the International Conference onAlzheimer's Disease, Chicago, Ill., USA, July 2008; paper S4-04-05.).Hung and coworkers (Hung, D. Dimebon: A phase 3 investigational agentfor Alzheimer's disease with a novel mitochondrial mechanism of action.Presented at the International Conference on Alzheimer's Disease,Chicago, Ill., USA, July 2008; paper S4-04-05) reported that dimebolincan protect cells from excitotoxic damage and improve neurite outgrowthin neuroblastoma cell lines and primary neurons. From an adverse effectstandpoint, in recently reported clinical studies of dimebolin, the mostfrequent adverse event was dry mouth, which is consistent with theantihistaminic effects of dimebolin (Doody, R. S.; Gavrilova, S. I.; etal. Effect of dimebon on cognition, activities of daily living,behaviour, and global function in patients with mild-to-moderateAlzheimer's disease: a randomised, double-blind, placebo-controlledstudy. Lancet 2008, 372(9634), 207-215.). There is a need in the art toidentify and provide novel agents for treating or preventing conditionsassociated neurodegenerative disorders such as AD, lacking histaminergic(H1) interactions.

As noted earlier, given the likely multiple etiologies ofneurodegenerative diseases such as AD, multiple approaches are beingpursued as symptomatic approaches or as disease modifying approaches toalter the underlying pathology of the disease (Scatena, R.; Martorana,G. E.; et al. An update on pharmacological approaches toneurodegenerative diseases. Expert Opin. Invest. Drugs 2007, 16(1),59-72.). In particular, the reported benefit of dimebolin indouble-blind, placebo-controlled study of patients with mild-to-moderateAD across many cognitive and clinical measures demonstrates thepotential of such compounds to prevent or treat a variety ofneurodegenerative diseases where an underlying pathology involvesdeficits in cognitive function. In addition to the need for improvedreceptor selectivity profile (as for example vs. H1 receptors), one ofthe current limitations with dimebolin is the dosing regimennecessitating three times per day (t.i.d.) administration in humans. Asneuroprotective approaches exemplified by dimebolin continue to bevalidated as a viable clinical approach, there is a need in the art toidentify and provide novel compounds for treating or preventingcognitive deficits associated with AD and other neurodegenerative andneuropsychiatric diseases.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds of having aformula of (I), (II), (III), (IV), (V), or (VI):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

a is a single or double bond;

X is CHR⁶, C═CHR⁶, or NR⁶;

X¹ is CHR⁸ or NR⁸;

U, V, W, and Y are each independently —(CH₂)_(p)—;

-   -   p at each occurrence is independently 0, 1, or 2;

Z is —(CH₂)_(q)—;

-   -   q is 1, 2, or 3;

R¹, R², R³, and R⁴ are each independently hydrogen, alkyl, alkenyl,alkynyl, halogen, cyano, -G¹, —N(R^(b))(R^(3a)), —N(R^(a))C(O)R^(1a),—N(R^(a))C(O)O(R^(1a)), —N(R^(a))C(O)N(R^(b))(R^(3a)), —OR^(1a),—SR^(1a), —S(O)₂R^(2a), or haloalkyl; wherein

-   -   R^(a) and R^(b), at each occurrence, are each independently        hydrogen, alkyl, or haloalkyl;    -   R^(1a) and R^(3a), at each occurrence, are each independently        hydrogen, alkyl, haloalkyl, G¹, or —(CR^(6a)R^(7a))_(n)-G¹;    -   R^(2a), at each occurrence, is independently alkyl, haloalkyl,        G¹, or —(CR^(6a)R^(7a))_(n)-G¹;    -   n, at each occurrence, is independently 1, 2, 3, 4, or 5;    -   R^(6a) and R^(7a), at each occurrence, are each independently        hydrogen, halogen, alkyl, or haloalkyl;    -   G¹, at each occurrence, is independently aryl, heteroaryl,        heterocycle, or cycloalkyl, wherein each G¹ is independently        unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        halogen, cyano, oxo, —NO₂, —OR^(1b), —OC(O)R^(1b),        —OC(O)N(R^(b))(R^(3b)), —SR^(1b), —S(O)₂R^(2b),        —S(O)₂N(R^(b))(R^(3b)), —C(O)R^(1b), —C(O)OR^(1b),        —C(O)N(R^(b))(R^(3b)), —N(R^(b))(R^(3b)), —N(R^(a))C(O)R^(1b),        —N(R^(a))C(O)O(R^(1b)), —N(R^(a))C(O)N(R^(b))(R^(3b)),        —(CR^(4b)R^(5b))_(m)—NO₂, —(CR^(4b)R^(5b))_(m)—OR^(1b),        —(CR^(4b)R^(5b))_(m)—OC(O)R^(1b),        —(CR^(4b)R^(5b))_(m)—OC(O)N(R^(b))(R^(3b)),        —(CR^(4b)R^(5b))_(m)—SR^(1b), —(CR^(4b)R^(5b))_(m)—S(O)₂R^(2b),        —(CR^(4b)R^(5b))_(m)—S(O)₂N(R^(b))(R^(3b)),        —(CR^(4b)R^(5b))_(m)—C(O)R^(1b),        —(CR^(4b)R^(5b))_(m)—C(O)OR^(1b),        —(CR^(4b)R^(5b))_(m)—C(O)N(R^(b))(R^(3b)),        —(CR^(4b)R^(5b))_(m)—N(R^(b))(R^(3b)),        —(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)R^(1b),        —(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)O(R^(b)),        —(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)N(R^(b))(R^(3b)), cyanoalkyl,        and haloalkyl;    -   m, at each occurrence, is independently 1, 2, 3, 4, or 5;    -   R^(1b) and R^(3b), at each occurrence, are each independently        hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, haloalkyl,        heteroarylalkyl, or heterocyclealkyl;    -   R^(2b), at each occurrence, is independently alkyl or haloalkyl;    -   R^(4b) and R^(5b), at each occurrence, are each independently        hydrogen, halogen, alkyl, or haloalkyl;

R⁵ is hydrogen, alkyl, -G¹, —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)),—C(O)R^(1a), —C(O)OR^(1a), —C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—NO₂, —(CR^(4a)R^(5a))_(m)—OR^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)),(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)-G¹, cyanoalkyl, or haloalkyl;

-   -   R^(4a) and R^(5a), at each occurrence, are each independently        hydrogen, halogen, alkyl, or haloalkyl;

R⁶ is alkyl, —S(O)₂R^(2a), —C(O)R^(1a), —C(O)OR^(1a),—C(O)N(R^(b))(R^(3a)), —(CR^(4a)R^(5a))_(m)—NO₂,—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G²-G¹,—CR^(4a)═CR^(5a)—S(O)₂R^(2a), —CR^(4a)═CR^(5a)—S(O)₂N(R^(b))(R^(3a)),—CR^(4a)═CR^(5a)—C(O)R^(1a), —CR^(4a)═CR^(5a)—C(O)OR^(1a),—CR^(4a)═CR^(5a)-G¹, -G¹, -G²-G¹, cyanoalkyl, or haloalkyl;

G² is aryl, heteroaryl, heterocycle, or cycloalkyl unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, halogen, cyano, oxo, —NO₂,—OR^(1b), —OC(O)R^(1b), —OC(O)N(R^(b))(R^(3b)), —SR^(1b), —S(O)₂R^(2b),—S(O)₂N(R^(b))(R^(3b)), —C(O)R^(1b), —C(O)OR^(1b),—C(O)N(R^(b))(R^(3b)), —N(R^(b))(R^(3b)), —N(R^(a))C(O)R^(1b),—N(R^(a))C(O)O(R^(1b)), —N(R^(a))C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—NO₂, —(CR^(4b)R^(5b))_(m)—OR^(1b),—(CR^(4b)R^(5b))_(m)—OC(O)R^(1b),—(CR^(4b)R^(5b))_(m)—OC(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—SR^(1b), —(CR^(4b)R^(5b))_(m)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(m)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—C(O)R^(1b), —(CR^(4b)R^(5b))_(m)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(m)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)N(R^(b))(R^(3b)), cyanoalkyl, andhaloalkyl;

R⁷ is hydrogen, alkyl, -G¹, —(CR^(4a)R^(5a))_(m)—NO₂,—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)-G¹, cyanoalkyl, or haloalkyl; and

R⁸ is —(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G²-G¹, or—CR^(4a)═CR^(5a)-G¹;

with the proviso that in a compound of formula (I),

when R¹, R² and R⁴ are each hydrogen;

R³ is hydrogen or halogen;

U is CH₂;

V, W, and Y are each —(CH₂)_(p)—, wherein p is 0;

Z is —(CH₂)_(q)—, wherein q is 2 or 3;

X is NR⁶; and

R⁶ is alkyl, -G¹, or —(CR^(4a)R^(5a))_(m)-G¹, wherein m is 1, R^(4a) andR^(5a) are hydrogen and G¹ is phenyl unsubstituted or substituted withalkyl, halogen, hydroxy or —OR^(1a) wherein R^(1a) is alkyl;

R⁵ is other than hydrogen, alkyl, —(CR^(4a)R^(5a))_(m)-G¹, —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), or —(CR^(4a)R^(5a))_(m)—C(O)R^(1a) whereinR^(1a) is alkyl, aryl, or heteroaryl, and G¹ is aryl or heteroaryl; or

with the proviso that in a compound of formula (IV),

when a is a double bond;

V is —(CH₂)_(p)—, wherein p is 0;

Y is —(CH₂)_(p)—, wherein p is 2;

Z is —(CH₂)_(q)—, wherein q is 1; and

X is NR⁶, then

R⁶ is other than alkyl, C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a),—(CR^(4a)R^(5a))_(m)C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—N(R^(b))(R3a),—(CR^(4a)R^(5a))_(m)-G¹, —CR^(4a)═CR^(5a)-G¹, -G¹, cyanoalkyl orhaloalkyl.

The present invention further provides processes of making the compoundsof the present invention, and intermediates employed in the processes.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of at leastone compound(s) having a formula of (I), (II), (III), (IV), (V), or (VI)described above or pharmaceutically acceptable salts thereof, incombination with at least one pharmaceutically acceptable carrier.

In yet another aspect, the present invention relates to a method ofpreventing or treating a neurodegeneration disorder using a compound offormula (I), (II), (III), (IV), (V), or (VI). Such methods involvesadministering a therapeutically effective amount of at least onecompound of formula (I), (II), (III), (IV), (V) or (VI) to a subject inneed of treatment thereof. Examples of neurodegeneration disorders areAlzheimer's disease (AD), mild cognitive impairment (MCI),age-associated memory impairment (AAMI), multiple sclerosis, Parkinson'sdisease, vascular dementia, senile dementia, AIDS dementia, Pick'sdisease, dementia caused by cerebrovascular disorders, corticobasaldegeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease,diminished CNS function associated with traumatic brain injury or anycombinations thereof. The above method also further comprisesadministering a cognitive enhancing drug to the subject. The cognitiveenhancing drug can be administered simultaneously or sequentially withthe compound of formula (I), (II), (III), (IV), (V), or (VI).

In yet another aspect, the present invention relates to a method ofpreventing or treating a neuropsychiatric disorder using a compound offormula (I), (II), (III), (IV), (V), or (VI). Such methods involveadministering a therapeutically effective amount of at least onecompound of formula (I), (II), (III), (IV), (V) or (VI), to a subject inneed of treatment thereof. Examples of neuropsychiatric disorders areschizophrenia, cognitive deficits in schizophrenia, attention deficitdisorder, attention deficit hyperactivity disorder, bipolar and manicdisorders, depression or any combinations thereof. The above method alsofurther comprises administering a cognitive enhancing drug to thesubject. The cognitive enhancing drug can be administered simultaneouslyor sequentially with the compound of formula (I), (II), (III), (IV),(V), or (VI).

In a further aspect, the present invention relates to methods ofpreventing or treating a pain condition using a compound of formula (I),(II), (III), (IV), (V), or (VI). Such methods include administering atherapeutically effective amount of at least one compound of formula(I), (II), (III), (IV), (V) or (VI), to a subject in need of treatmentthereof. Examples of pain conditions includes neuropathic andnociceptive pain, chronic or acute, such as, without limitation,allodynia, inflammatory pain, inflammatory hyperalgesia, post herpeticneuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-relatedneuropathy, nerve injury, rheumatoid arthritic pain, osteoarthriticpain, burns, back pain, ocular pain, visceral pain, cancer pain, dentalpain, headache, migraine, carpal tunnel syndrome, fibromyalgia,neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post operativepain, post stroke pain, and menstrual pain.

The present invention can also include use of a compound of formula (I),(II), (III), (IV), (V), or (VI) as neuroprotective agent for theprevention or treatment of a neurological disorder or condition. Themethod includes administering a therapeutically effective amount of atleast one compound of formula (I), (II), (III), (IV), (V) or (VI), to asubject in need of treatment thereof. The neurological disorder orcondition can include, but is not limited to, neurodegenerationdisorders, neuropsychiatric disorder and pain conditions, braininjuries, stroke and other acute and chronic neuronal injuries ordegenerative conditions. The neurological disorder or condition caninclude, for example, conditions associated, at least in part, withmitochondrial dysfunction and/or neuronal apoptosis in the centralnervous system.

In still yet another aspect, the present invention relates to the use ofa compound of formula (I), (II), (III), (IV), (V), or (VI) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the prevention or treatment of the neurodegenerationdisorders described above, alone or in combination with at least onepharmaceutically acceptable carrier.

In still yet another aspect, the present invention relates to a methodof identifying one or more target compounds useful for treating aneurodegeneration disorder or a neuropsychiatric disorder. The methodcomprises the steps of:

a. providing a population of neuronal or neuroblastoma cells or celllines;

b. adding one or more target compounds to the population of neuronal orneuroblastoma cells or cell lines;

c. determining the neuronal number and neurite outgrowth after theaddition of the one or more target compounds; and

d. determining whether the one or more target compounds are useful fortreating a neurodegeneration disorder or a neuropsychiatric disorder.

In still yet another aspect, the present invention relates to a methodof identifying one or more target compounds useful for treating aneurodegeneration disorder or a neuropsychiatric disorder. The methodcomprises the steps of:

a. providing a population of neuronal or neuroblastoma cells or celllines;

b. adding one or more target compounds to the population of neuronal orneuroblastoma cells or cell lines;

c. determining mitochondrial membrane potential under serum-deprivationconditions; and

d. determining whether the one or more target compounds are useful fortreating a neurodegeneration disorder or a neuropsychiatric disorder.

The compounds of formula (I), (II), (III), (IV), (V), or (VI),compositions comprising these compounds, and methods for preventing ortreating neurodegenerative or neuropsychiatric disorders byadministering these compounds or pharmaceutical compositions are furtherdescribed herein.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a graphical representation of the concentration-dependenteffects of Example 1 on the number of neuron-like cells in nerve growthfactor-differentiated PC12 cells. Cells were treated with varyingconcentrations of the test compound (Example 1). Analysis was conducted24 hours post-treatment using high-content screen (HCS) microscopyanalysis system after staining with β-tubulin and Hoechst 33342. TheX-axis represents the test concentrations, and the Y-axis representspercent effects, normalized to 10 μM dimebolin.

FIG. 2 shows a graphical representation of the concentration-dependentneuroprotective effects of Example 5 on the percent increase of neuriteoutgrowth. In FIG. 2, a 100% response represents the neurite outgrowthof untreated cells. Cells (primary postnatal (P0) cortical cells)treated with Aβ₁₋₄₂ peptide showed a reduction in neurite outgrowth.Cells pretreated with varying concentrations of the test compound(Example 5) and then subsequently with test compounds and freshlyprepared Aβ₁₋₄₂ peptide showed neurite outgrowth levels similar to orenhanced relative to untreated control cells. The X-axis represents testconcentrations, and the Y-axis represents percent effects.

FIG. 3 shows a graphical representation of the concentration-dependentenhancement of mitochondrial function maintenance in the presence ofcellular stress. Maintenance of mitochondrial function in the presenceof stress prevents the initiation of apoptosis. SK-N-SH cells weretreated with varying concentrations of Example 5. Cellular function wasdetermined with a plate reader with an excitation and emission of 560 nMand 595 nM for red fluorescence and with an excitation and emission of485 nM and 535 nM for green fluorescence to determine the final JC-1value taking the red to green fluorescence ratio. The X-axis representsthe test concentrations, and the Y-axis represents mitochondrialfunction relative to 10 μM dimebolin (100% response).

FIG. 4 shows a graphical representation of the concentration-dependentimprovement in mouse 24-hour recall inhibitory avoidance scores upontreatment with test compound (Example 5). The X-axis represents the dayof exposure to condition, and the Y-axis represents the latency to crossto the punished side.

FIG. 5 shows a graphical representation of the concentration-dependentimprovement in rat social recognition ratio scores upon treatment withtest compound (Example 5). The X-axis represents the testconcentrations, and the Y-axis represents the recognition ratio (T2:T1).

FIG. 6 shows a graphical representation of the concentration-dependentimprovement in the treatment of neuropathic pain in rat with testcompound (Example 2). The X-axis represents the test concentrations, andthe Y-axis represents the pressure applied to elicit a pain response.

DETAILED DESCRIPTION

In one aspect, the present invention relates to compounds having aformula (I), (II), (III), (IV), (V), and (VI) as shown below:

wherein a, R¹, R², R³, R⁴, R⁵, U, V, W, X, Y, and Z are as defined abovein the Summary of the Invention.

In another aspect, the present invention relates to compositioncomprising compounds having a formula (I), (II), (III), (IV), (V), and(VI) as described above and at least one pharmaceutically acceptablecarrier.

In still yet another aspect, the present invention relates to methodsfor preventing and treating disease conditions, such asneurodegeneration disorders or neuropsychiatric disorders, usingcompounds having a formula of formula (I), (II), (III), (IV), (V), and(VI) as described above.

In still yet another aspect, the present invention relates to the use ofcompounds having a formula (I), (II), (III), (IV), (V), and (VI) in themanufacture of a medicament for the prevention or treatment of thedisease conditions, such as neurodegeneration disorders orneuropsychiatric disorders, described above, alone or in combinationwith at least one pharmaceutically acceptable carrier.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the present invention or any other formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

a. DEFINITIONS

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” denotes a divalent group derived from a straightor branched chain hydrocarbon of 2 to 4 carbon atoms and contains atleast one carbon-carbon double. Representative examples of alkyleneinclude, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁₋₆ alkyl” means a straight or branched chain hydrocarboncontaining 1 to 6 carbon atoms. The term “C₁₋₃ alkyl” means a straightor branched chain hydrocarbon containing 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain hydrocarbon 1 to 10 carbon atoms. Representative examplesof alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the aryl groups include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thebicyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the bicyclic ring system. The aryl groupsof the present invention can be unsubstituted or substituted.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocycliccycloalkyl fused to a monocyclic cycloalkyl ring, or a bridgedmonocyclic ring system in which two non-adjacent carbon atoms of themonocyclic ring are linked by an alkylene bridge containing one, two,three, or four carbon atoms. Representative examples of bicyclic ringsystems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic cycloalkylsare exemplified by a bicyclic cycloalkyl fused to a monocycliccycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbonatoms of the ring systems are linked by an alkylene bridge of 1, 2, 3,or 4 carbon atoms. Representative examples of tricyclic-ring systemsinclude, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonane(octahydro-2,5-methanopentalene or noradamantane), andtricyclo[3.3.1.1^(3,7)]decane (adamantane). The monocyclic, bicyclic,and tricyclic cycloalkyls can be unsubstituted or substituted, and areattached to the parent molecular moiety through any substitutable atomcontained within the ring system.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkyl include, butare not limited to, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. Thethree- or four-membered ring contains zero or one double bond, and oneheteroatom selected from the group consisting of O, N, and S. Thefive-membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. Thesix-membered ring contains zero, one or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.The seven- and eight-membered rings contains zero, one, two, or threedouble bonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyridazin-3(2H)-onyl,pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a bridged monocyclicheterocycle ring system in which two non adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, 1,4-benzoxazinyl, benzothiopyranyl, chromanyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heterocyclealkyl,” as used herein, means a heterocycle groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or abicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive-membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen orsulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, andtriazinyl. The bicyclic heteroaryl consists of a monocyclic heteroarylfused to a phenyl, or a monocyclic heteroaryl fused to a monocycliccycloalkyl, or a monocyclic heteroaryl fused to a monocycliccycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl, or a monocyclic heteroaryl fused to a monocyclicheterocycle. Representative examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, indazolyl, indolyl,isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,pyrido[1,2-a]pyrimidin-4-onyl, quinoxalinyl, quinazolinyl, quinolinyl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups of the present invention can be substituted or unsubstituted andare connected to the parent molecular moiety through any carbon atom orany nitrogen atom contained within the ring systems.

The term “heteroarylalkyl,” as used herein, means a heteroaryl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “heteroatom” as used herein, means a nitrogen, oxygen, orsulfur atom.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “oxo” as used herein, means a ═O group.

The term “pain”, as used herein, is understood to mean nociceptive painand neuropathic pain, both chronic and acute pain, including but notlimited to, osteoarthritis or rheumatoid arthritis pain, ocular pain,pains associated with intestinal inflammation, pains associated withcardiac muscle inflammation, pains associated with multiple sclerosis,pains associated with neuritis, pains associated with carcinomas andsarcomas, pains associated with AIDS, pains associated withchemotherapy, amputation pain, trigeminus neuralgia, headaches, such asmigraine cephalalgia, or neuropathic pains, such as post-herpes zosterneuralgia, post-injury pains and post-operative pains.

The term “sulfonyl” as used herein, means a —SO₂— group.

b. COMPOUNDS

Compounds of the present invention have the formula (I), (II), (III),(IV), (V), or (VI) as described above.

Particular values of variable groups in compounds of formula (I), (II),(III), (IV), (V), or (VI) are as follows. Such values may be used whereappropriate with any of the other values, definitions, claims orembodiments defined hereinbefore or hereinafter.

In one embodiment, R¹, R², R³, and R⁴ are each independently hydrogen,alkyl, alkenyl, alkynyl, halogen, cyano, -G¹, —N(R^(b))(R^(3a)),—N(R^(a))C(O)R^(1a), —N(R^(a))C(O)O(R^(1a)),—N(R^(a))C(O)N(R^(b))(R^(3a)), —OR^(1a), —SR^(1a), —S(O)₂R^(2a), orhaloalkyl; wherein R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, alkyl, or haloalkyl; R^(1a) and R^(3a), at eachoccurrence, are each independently hydrogen, alkyl, haloalkyl, G¹, or—(CR^(6a)R^(7a))_(n)-G¹; R^(2a), at each occurrence, is independentlyalkyl, haloalkyl, G¹, or —(CR^(6a)R^(7a))_(n)-G¹; R^(6a) and R^(7a), ateach occurrence, are each independently hydrogen, halogen, alkyl, orhaloalkyl; n, at each occurrence, is independently 1, 2, 3, 4, or 5; G¹is aryl, heteroaryl, heterocycle, or cycloalkyl, wherein each G¹ isindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halogen, cyano, oxo, —NO₂, —OR^(1b), —OC(O)R^(1b),—OC(O)N(R^(b))(R^(3b)), —SR^(1b), —S(O)₂R^(2b), —S(O)₂N(R^(b))(R^(3b)),—C(O)R^(1b), —C(O)OR^(1b), —C(O)N(R^(b))(R^(3b)), —N(R^(b))(R^(3b)),—N(R^(a))C(O)R^(1b), —N(R^(a))C(O)O(R^(1b)),—N(R^(a))C(O)N(R^(b))(R^(3b)), —(CR^(4b)R^(5b))_(m)—NO₂,—(CR^(4b)R^(5b))_(m)—OR^(1b), —(CR^(4b)R^(5b))_(m)—OC(O)R^(1b),—(CR^(4b)R^(5b))_(m)—OC(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—SR^(1b), —(CR^(4b)R^(5b))_(m)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(m)—S(O)₂N(R^(b))(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—C(O)R^(1b), —(CR^(4b)R^(5b))_(m)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(m)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(m)—N(R^(a))C(O)N(R^(b))(R^(3b)), cyanoalkyl, andhaloalkyl; R^(1b) and R^(3b), at each occurrence, are each independentlyhydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, haloalkyl,heteroarylalkyl, or heterocyclealkyl; R^(2b), at each occurrence, isindependently alkyl or haloalkyl; R^(4b) and R^(5b), at each occurrence,are each independently hydrogen, halogen, alkyl, or haloalkyl; and m ateach occurrence, is independently 1, 2, 3, 4, or 5.

In another embodiment, R¹, R², R³, and R⁴ are each independentlyhydrogen, alkyl, haloalkyl, halogen, -G¹, —OR^(1a), or —SO₂R^(2a).

In another embodiment, R¹, R², R³, and R⁴ are each independentlyhydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy, cyclopropyl,alkylsulfonyl, pyridyl, pyrazolyl, or aryl optionally substituted withhalogen or haloalkyl.

In a further embodiment, R¹, R², and R⁴ are hydrogen, and R³ is alkyl.

In a further embodiment, R¹, R², and R⁴ are hydrogen, and R³ is halogen.

In a further embodiment, R¹, R², and R⁴ are hydrogen, and R³ isfluorine.

In a further embodiment, R¹, R², R³ and R⁴ are each hydrogen.

In one embodiment, R⁵ is hydrogen, alkyl, -G¹, —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —C(O)OR^(1a),—C(O)N(R^(b))(R^(3a)), —(CR^(4a)R^(5a))_(m)—NO₂,—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(b))(R^(3a)),(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)-G¹, cyanoalkyl, or haloalkyl; wherein R^(1a) andR^(3a), at each occurrence, are independently hydrogen, alkyl,haloalkyl, G¹, or —(CR^(6a)R^(7a))_(n)-G¹; R^(2a), at each occurrence,is independently alkyl, haloalkyl, G¹, or —(CR^(6a)R^(7a))_(n)-G¹;R^(4a), R^(5a), R^(6a) and R^(7a), at each occurrence, are eachindependently hydrogen, halogen, alkyl, or haloalkyl; and R^(a), R^(b),m, n, and G¹ are as disclosed in the Summary of the Invention and theembodiments described herein.

In another embodiment, R⁵ is hydrogen, alkyl, haloalkyl, —C(O)R^(1a),C(O)R^(1a) or S(O)₂R^(2a).

In an additional embodiment, R⁵ is hydrogen.

In an additional embodiment, R⁵ is —C(O)R^(1a), C(O)OR^(1a) orS(O)₂R^(2a).

In a further embodiment, R⁵ is —C(O)R^(1a), wherein R^(1a) is phenyloptionally substituted with alkyl or halogen.

In a further embodiment, R⁵ is —C(O)OR^(1a), wherein R^(1a) is alkyl.

In a further embodiment, R⁵ is S(O)₂R^(2a), wherein R^(2a) is phenyloptionally substituted with alkyl, halogen or haloalkyl.

In a further embodiment, R⁵ is alkyl or haloalkyl.

In one embodiment, X is CHR⁶, C═CHR⁶, or NR⁶.

In a further embodiment, X is NR⁶.

In one embodiment, X¹ is CHR⁸, or NR⁸.

In another embodiment, X¹ is CHR⁸.

In a further embodiment, X¹ is NR⁶.

In one embodiment, R⁶ is alkyl, —S(O)₂R^(2a), —C(O)R^(1a), —C(O)OR^(1a),—C(O)N(R^(b))(R^(3a)), —(CR^(4a)R^(5a))_(m)—NO₂,—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(b))(R^(3a)),(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G²-G¹,—CR^(4a)═CR^(5a)—S(O)₂R^(2a), —CR^(4a)═CR^(5a)—S(O)₂N(R^(b))(R^(3a)),—CR^(4a)═CR^(5a)—C(O)R^(1a), —CR^(4a)═CR^(5a)—C(O)OR^(1a),—CR^(4a)═CR^(5a)-G¹, -G¹, -G²-G¹; cyanoalkyl, or haloalkyl, whereinR^(a), R^(1a), R^(2a), R^(3a), R^(4a), R^(5a), R^(b), m, G¹, and G² areas disclosed in the Summary of the Invention and the embodimentsdescribed herein.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)-G¹, wherein R^(4a) andR^(5a) are each hydrogen; m is 1, 2 or 3; and G¹ is as disclosed in theSummary of the Invention and the embodiments described herein.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)-G¹, wherein R^(4a) andR^(5a) are each hydrogen; m is 1 or 2; and G¹ is phenyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyridazin-3(2H)-one, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 1H-benzimidazol-2-yl, quinolin-8-yl,thiazolyl, 1,2-oxazol-5-yl, 1,4,5,6-tetrahydropyrimidin-5-yl,imidazo[1,2-b]pyridazin-2-yl, or imidazo[1,2-a]pyrimidin-2-yl; whereinG¹ is independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, halogen,—N(R^(b))(R^(3b)), and haloalkyl; R^(b) is hydrogen or alkyl; and R^(3b)is hydrogen, alkoxyalkyl, alkyl, arylalkyl, heteroarylalkyl, orheterocyclealkyl.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)-G¹, wherein one ofR^(4a) or R^(5a) is alkyl and the others of R^(4a) and R^(5a) arehydrogen; m is 1, 2 or 3; and G¹ is optionally substituted phenyl orpyridyl.

In a further embodiment, R⁶ is —CH₂CH₂-(6-methylpyridin-3-yl).

In another embodiment, R⁶ is —CR^(4a)═CR^(a)-G¹, wherein R^(4a) andR^(5a) are each hydrogen, and G¹ is as disclosed in the Summary of theInvention and the embodiments described herein.

In another embodiment, R⁶ is —CR^(4a)═CR^(5a)-G¹, wherein R^(4a) andR^(5a) are each hydrogen, and G¹ is optionally substituted pyridyl orphenyl.

In a further embodiment, R⁶ is —CH═CH-(6-methylpyridin-3-yl).

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)-G²-G¹, wherein R^(4a)and R^(5a) are at each occurrence hydrogen; m is 1; and G² is oxazolyl,pyridyl, pyrimidinyl, or phenyl; and G¹ is oxadiazolyl, pyrrolidinyl,piperidinyl, pyrazolyl, pyridazin-3(2H)-onyl, or phenyl, optionallyunsubstituted or substituted with 1, 2, or 3 alkyl, haloalkyl orhalogen.

In another embodiment, R⁶ is -G²-G¹, wherein G² is optionallysubstituted aryl or optionally substituted heteroaryl, and G¹ is asdisclosed in the Summary of the Invention and the embodiments describedherein.

In a another embodiment, R⁶ is -G²-G¹, wherein G² is a pyridazinyl andG¹ is optionally substituted aryl or optionally substituted heteroaryl.

In a another embodiment, R⁶ is -G²-G¹, wherein G² is a pyridinyl and G¹is optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocycle.

In a further embodiment, R⁶ is -G²-G¹, wherein G² is a phenyl,pyridinyl, or pyridazinyl, and G¹ is optionally substituted phenyl,pyrazolyl, pyridazin-3(2H)-onyl, morpholinyl, piperazinyl, orimidazolyl.

In a further embodiment, R⁶ is -G²-G¹, wherein G² is a phenyl and G¹ isoptionally substituted aryl, optionally substituted heterocycle, oroptionally substituted heteroaryl.

In another embodiment, R⁶ is —C(O)R^(1a), wherein R^(1a) is as disclosedin the Summary of the Invention.

In a further embodiment, R⁶ is —C(O)R^(1a), wherein R^(1a) is—(CR^(6a)R^(7a))_(n)-G¹, wherein R^(6a), R^(7a), n and G¹ are asdisclosed in the Summary of the Invention.

In a further embodiment, R⁶ is —C(O)R^(1a), wherein R^(1a) is—(CR^(6a)R^(7a))_(n)-G¹, wherein R^(6a), R^(7a) are each hydrogen, n is1, and G¹ is optionally substituted phenyl.

In another embodiment, R⁶ is G¹, wherein G¹ is as disclosed in theSummary of the Invention.

In a further embodiment, R⁶ is G¹, wherein G¹ is optionally substitutedaryl or heteroaryl.

In a further embodiment, R⁶ is G¹, wherein G¹ is optionally substitutedquinazolinyl, quinoxalin-2(1H)-onyl, pyrido[1,2-a]pyrimidinyl,pyrimidinyl, pyridyl, tetrahydroisoquinolinyl, quinazolinyl,isoquinolinyl, quinoxalinyl, benzoxazinyl, phenyl,pyrido[1,2-a]pyrimidinyl, quinolinyl, or pyrido[1,2-a]pyrimidin-4-onyl.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)—OR^(1a), whereinR^(1a), R^(4a), R^(5a), and m are as disclosed in the Summary of theInvention.

In a further embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)—OR^(1a), whereinR^(4a), R^(5a), and m are as disclosed in the Summary of the Invention,and R^(1a) is G¹, wherein G¹ is as described in the Summary of theInvention.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)—OR^(1a), whereinR^(1a) is phenyl optionally substituted with alkyl, halogen, or OR^(1b),wherein R^(1b) is alkyl or haloalkyl; R^(4a) and R^(5a) are hydrogen ateach occurrence, and m is 1 or 2.

In another embodiment, R⁶ is —S(O)₂R^(2a), wherein R^(2a) is asdescribed in the Summary of the Invention.

In a further embodiment, R⁶ is —S(O)₂R^(2a), wherein R^(2a) is as G¹,wherein G¹ is as described in the Summary of the Invention.

In a further embodiment, R⁶ is —S(O)₂R^(2a), wherein R^(2a) is as G¹,wherein G¹ is phenyl, or pyridyl, optionally substituted with alkyl,halogen, or haloalkyl.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a) or—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)), wherein R^(1a), R^(3a),R^(4a), R^(5a), m, and R^(b) are as disclosed in the Summary of theInvention.

In a further embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a) or—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)), wherein R^(1a) and R^(3a) areeach independently G¹, wherein G¹ is as described in the Summary of theInvention, and R^(4a), R^(5a), m, and R^(b) are as disclosed in theSummary of the Invention.

In a further embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a), whereinR^(1a) is alkyl; R^(4a) and R^(5a) are hydrogen at each occurrence; andm is 1 or 2.

In a further embodiment, R⁶ is—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)), wherein R^(3a) is optionallysubstituted phenyl; R^(4a) and R^(5a) are hydrogen at each occurrence; mis 1 or 2; and R^(b) is hydrogen.

In another embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)-G²-G¹, wherein R^(4a),R^(5a), m, G¹, and G² are as disclosed in the Summary of the Invention.

In a further embodiment, R⁶ is —(CR^(4a)R^(5a))_(m)-G²-G¹, whereinR^(4a), R^(5a), and m are as disclosed in the Summary of the Inventionand G¹ and G² are independently optionally substituted aryl orheteroaryl.

In one embodiment, R⁷ is hydrogen, alkyl, -G¹, —(CR^(4a)R^(5a))_(m)—NO₂,—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)-G¹, cyanoalkyl, or haloalkyl.

In a further embodiment, R⁷ is hydrogen, alkyl, or haloalkyl.

In one embodiment, R⁸ is —(CR^(4a)R^(5a))_(m)-G¹,—(CR^(4a)R^(5a))_(m)-G²-G¹, or —CR^(4a)═CR^(5a)-G¹.

In another embodiment, R⁸ is —(CR^(4a)R^(5a))_(m)-G¹.

In a further embodiment, R⁸ is —CR^(4a)═CR^(5a)-G¹.

Compounds of formula (I) can include, but are not limited to, compoundswherein a is a single or double bond. Thus, compounds within formula (I)include compounds having the following formula (Ia) and (Ib) andpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵, U, V, W, X, Y, and Z are as disclosed in theSummary of the Invention and the embodiments described herein.

Compounds of formula (I) can include, but are not limited to, compoundswherein U is —(CH₂)_(p)—, wherein p is 1; V, W, and Y are each—(CH₂)_(p)—, wherein p is 0, i.e., a bond; and Z is —(CH₂)_(q)—, whereinq is 2.

Compounds of formula (I) can also include, but are not limited to,compounds wherein U is —(CH₂)_(p)—, wherein p is 1; V, W, and Y are each—(CH₂)_(p)—, wherein p is 0, i.e., a bond; and Z is —(CH₂)_(q)—, whereinq is 3.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, and W are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;Y is —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—, wherein q is 1.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, and W are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;Y is —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—, wherein q is 2.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, and Y are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;W is —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—, wherein q is 1.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, and Y are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;W is —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—, wherein q is 2.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, W, and Y are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;V is —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—, wherein q is 2.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, W, and Y are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;V is —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—, wherein q is 3.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, W, and Y are each —(CH₂)_(p)—, wherein p is 0, i.e., abond; and Z is —(CH₂)_(q)—, wherein q is 2.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, and W are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond;Y is —(CH₂)_(p)—, wherein p is 2; and Z is —(CH₂)_(q)—, wherein q is 1.

Compounds of formula (I) can include, but are not limited to, compoundswherein V and W are each —(CH₂)_(p)—, wherein p is 0, i.e., a bond; andU and Y are each —(CH₂)_(p)—, wherein p is 1; and Z is —(CH₂)_(q)—,wherein q is 1.

Compounds of formula (I) can include, but are not limited to, compoundswherein U, V, W, and Y are each —(CH₂)_(p)—, wherein p is 0, i.e., abond; and Z is —(CH₂)_(q)—, wherein q is 3.

In another embodiment, in compounds of formula (I), wherein R¹, R² andR⁴ are each hydrogen; R³ is hydrogen or halogen; U is CH₂; V, W, and Yare each —(CH₂)_(p)—, wherein p is 0, i.e., a bond; Z is —(CH₂)_(q)—,wherein q is 2 or 3; X is NR⁶; and R⁶ is alkyl, -G¹, or—(CR^(4a)R^(5a))_(m)-G¹, wherein m is 1, R^(4a) and R^(5a) are hydrogenand G¹ is phenyl unsubstituted or substituted with alkyl, halogen,hydroxy or —OR^(1a) wherein R^(1a) is alkyl; R⁵ is other than hydrogen,alkyl, —(CR^(4a)R^(5a))_(m)-G¹, —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), or —(CR^(4a)R^(5a))_(m)—C(O)R^(1a) whereinR^(1a) is alkyl, aryl, or heteroaryl, and G¹ is aryl or heteroaryl.

Compounds of formula (II) can include, but are not limited to, compoundswherein R¹, R², R³, R⁴, R⁷, W, X¹, and Y are as disclosed in the Summaryof the Invention and the embodiments described herein andpharmaceutically acceptable salts thereof.

Compounds of formula (II) can include, but are not limited to, compoundswherein one of W and Y is —(CH₂)_(p)—, wherein p is 0, i.e., a bond andthe other is —(CH₂)_(p)—, wherein p is 1.

Compounds of formula (II) can include, but are not limited to, compoundswherein one of W and Y is —(CH₂)_(p)—, wherein p is 0, i.e., a bond andthe other is —(CH₂)_(p)—, wherein p is 2.

Compounds of formula (III) can include, but are not limited to,compounds wherein R¹, R², R³, R⁴, X, and Z are as disclosed in theSummary of the Invention and the embodiments described herein andpharmaceutically acceptable salts thereof.

Compounds of formula (IV) can include, but are not limited to, compoundswherein a is a single or double bond. Thus, compounds within formula(IV) include compounds of the following formula (IVa) and (IVb) andpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, V, X, and Z are as disclosed in the Summary ofthe Invention and the embodiments described herein.

Compounds of formula (IVa) can include, but are not limited to,compounds wherein V and Y are each —(CH₂)_(p)—, wherein p is 1; and Z is—(CH₂)_(q)—, wherein q is 1.

Compounds of formula (IVa) can include, but are not limited to,compounds wherein V is —(CH₂)_(p)—, wherein p is 1; Y is —(CH₂)_(p)—,wherein p is 2; and Z is —(CH₂)_(q)—, wherein q is 1.

Compounds of formula (IVa) can include, but are not limited to,compounds wherein V and Y are each —(CH₂)_(p)—, wherein p is 1; and Z is—(CH₂)_(q)—, wherein q is 2.

Compounds of formula (IVa) can include, but are not limited to,compounds wherein V is —(CH₂)_(p)—, wherein p is 0, i.e., a bond; Y is—(CH₂)_(p)—, wherein p is 2; and Z is —(CH₂)_(q)—, wherein q is 1.

Compounds of formula (IVb) can include, but are not limited to,compounds wherein V, Y, and Z are each CH₂.

Compounds of formula (IVb) can include, but are not limited to,compounds wherein V and Y are each —(CH₂)_(p)—, wherein p is 1; and Z is—(CH₂)_(q)—, wherein q is 2.

In another embodiment, in compounds of formula (IVb), wherein V is—(CH₂)_(p)—, wherein p is 0, i.e., a bond; Y is —(CH₂)_(p)—, wherein pis 2; and Z is —(CH₂)_(q)—, wherein q is 1; R⁶ is other than alkyl,C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a),—(CR^(4a)R^(5a))_(m)C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—N(R^(b))(R3a),—(CR^(4a)R^(5a))_(m)-G¹, —CR^(4a)═CR^(5a)-G¹, -G¹, cyanoalkyl orhaloalkyl.

Compounds of formula (IVb) can include, but are not limited to,compounds wherein V and Z are each CH₂; and Y is CH₂CH₂.

Compounds of formula (V) can include, but are not limited to, compoundswherein R¹, R², R³, R⁴, and X are as disclosed in the Summary of theInvention and the embodiments described herein and pharmaceuticallyacceptable salts thereof.

Compounds of formula (VI) can include, but are not limited to, compoundswherein a is a single or double bond. Thus, compounds within formula(VI) include compounds of the following formula (VIa) and (VIb) andpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, and X are as disclosed in the Summary of theInvention and the embodiments described herein.

Specific embodiments of compounds contemplated as part of the inventioninclude, but are not limited to:

-   2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   5-[6-(4-iodophenyl)pyridazin-3-yl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indole;-   2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-1,4-methanopyrido[4,3-b]indole;-   6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-4,1-(epiminomethano)carbazole;-   2,6-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-1,4-methano-β-carboline;-   6,11-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-1,4-(epiminomethano)carbazole;-   2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-6,9-epiminocyclohepta[b]indole;-   2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-6,10-epiminocycloocta[b]indole;-   6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-1,4-epiminocarbazole;-   2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,6-hexahydro-1,5-methanoazepino[4,3-b]indole;-   2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole;-   2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;-   (5aS*,7S*,10R*,10aR*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole;-   (5aR*,7S*,10R*,10aS*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole;-   (5aS*,7S*,11R*,11aR*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-7,11-epiminocycloocta[b]indole;-   (5aR*,7S*,11R*,11aS*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-7,11-epiminocycloocta[b]indole;-   (5R*,5aS*,10bR*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-methanoazepino[4,3-b]indole;-   (5R*,5aR*,10bS*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-methanoazepino[4,3-b]indole;-   (1R*,4R*,4aS*,9bR*)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-1,4-methanopyrido[4,3-b]indole;-   (1R*,4R*,4aR*,9bS*)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-1,4-methanopyrido[4,3-b]indole;-   (1R*,4R*,4aR*,9aS*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-4,1-(epiminomethano)carbazole;-   (1R*,4R*,4aS*,9aR*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-4,1-(epiminomethano)carbazole;-   (1S*,4R*,4aS*,9aR*)-2,6-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-H-1,4-methano-β-carboline;-   (1S*,4R*,4aR*,9aS*)-2,6-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-H-1,4-methano-β-carboline;-   (1S*,4R*,4aS*,9aR*)-6,11-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-(epiminomethano)carbazole;-   (1S*,4R*,4aR*,9aS*)-6,11-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-(epiminomethano)carbazole;-   (5aR*,6S*,9R*,10aS*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,9-epiminocyclohepta[b]indole;-   (5S*,6S*,9R*,10aR*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,9-epiminocyclohepta[b]indole;-   (5aR*,6S*,10R*,11S*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-6,10-epiminocycloocta[b]indole;-   (5S*,6S*,10R*,11aR*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-6,10-epiminocycloocta[b]indole;-   (1R*,4S*,4aR*,9aR*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-epiminocarbazole;-   (1R*,4S*,4aS*,9aS*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-epiminocarbazole;-   (1R*,5S*,5aS*,10bR*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,5-methanoazepino[4,3-b]indole;-   (1R*,5S*,5aR*,10bS*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,5-methanoazepino[4,3-b]indole;-   (1R*,4S*,5    S*,10bR*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,    4-methanoazepino[4,3-b]indole;-   (1R*,4S*,5aR*,10bS*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,    4-methanoazepino[4,3-b]indole;-   (5aR*,6R*,10S*,10aR*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,10-epiminocyclohepta[b]indole;-   (5aS*,6R*,10S*,10aS*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,10-epiminocyclohepta[b]indole;-   1′,5-dimethyl-1-[2-(6-methylpyridin-3-yl)ethyl]-1,2-dihydrospiro[indole-3,3′-pyrrolidine];-   1′,5-dimethyl-1-[2-(6-methylpyridin-3-yl)ethyl]-1,2-dihydrospiro[indole-3,3′-piperidine];-   2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-ethyl-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-(2-fluoroethyl)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-11-(2,2,2-trifluoroethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   ethyl    (7R,10S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate;-   ethyl    (7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate;-   11-(4-chlorobenzoyl)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-11-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[2-(2-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-[(Z)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[(E)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[(E)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-(2-pyridin-2-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-[2-(5-ethylpyridin-2-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-(2-pyridin-4-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-(2-pyrimidin-5-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[2-(6-methylpyridazin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[2-(5-methylpyrazin-2-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(3-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(2-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-[2-(2-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-bromophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(3-bromophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-{2-[4-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-methoxyphenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[(E)-2-phenylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-[(E)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[(E)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-[(Z)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[(Z)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-[(E)-2-(2,4-dimethylphenyl)vinyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[(4-chlorophenyl)acetyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)propyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-(4-isopropenylphenyl)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-(3-phenylpropyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-fluorophenoxy)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-isoquinolin-7-yl-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-(phenylsulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2,11-dimethyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2,11-dimethyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[(4-fluorophenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[(4-chlorophenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[(4-methoxyphenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2,11-dimethyl-5-(pyridin-3-ylsulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-[2-(2-methyl-1,4,5,6-tetrahydropyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-fluoro-11-methyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-fluoro-5-[2-(4-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-fluoro-5-[2-(3-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-bromo-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-methoxy-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-2-methoxy-11-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-2-methoxy-11-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)ethyl]-4-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethoxy)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-isopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-cyclopropyl-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-cyclopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-tert-butyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-tert-butyl-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-(4-chlorophenyl)-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-bromo-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   2-(4-chlorophenyl)-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-pyridin-3-yl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-pyridin-3-yl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-(1H-pyrazol-4-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (5aS,7S,10R,10aR)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole;-   2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   5-[2-(6-chloropyridin-3-yl)ethyl]-2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   2,12-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2,12-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2,12-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2-methyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2-methyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2-methyl-5-[2-(2-methylphenyl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2-methyl-5-[2-(2-methylphenyl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-5-[2-(2,5-dimethylphenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-5-[2-(2,5-dimethylphenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-5-[2-(4-chlorophenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-5-[2-(4-chlorophenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   12-ethyl-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7R,11S)-2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   (7S,11R)-2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   2-methyl-5-{(Z)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   5-[2-(6-methylpyridin-3-yl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   5-[2-(2-methylphenyl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;-   6-[2-(6-chloropyridin-3-yl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[(E)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[(Z)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[2-(6-methylpyridazin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[2-(2-methylphenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[2-(2-fluorophenyl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[2-(4-chlorophenyl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-{2-[3-(trifluoromethyl)phenyl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-[(Z)-2-(4-methylphenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   ethyl    (9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetate;-   N-(4-chlorophenyl)-2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetamide;-   2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-N-[4-(trifluoromethoxy)phenyl]acetamide;-   (5aR*,10bS*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   (5aS,10bR)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   (5aR,10bS)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[2-(4-fluorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(4-fluorobenzyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(4-chlorobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(4-bromobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[3-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(2,3-difluoro-4-methylbenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[3-fluoro-4-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[(2-phenyl-1,3-oxazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-bromo-6-[2-(4-chlorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(E)-2-pyridin-3-ylvinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[2-(6-methylpyridin-3-yl)ethyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[2-(6-methylpiperidin-3-yl)ethyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[2-(6-methylpyridin-3-yl)ethyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(pyridin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(pyridin-4-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(pyridin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(pyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   8-[(6-chloropyridin-3-yl)methyl]-11-fluoro-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;-   9-fluoro-6-[(2-fluoropyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;-   (1R*,7R*,7aS*,12bR*)-11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,7a,8,12b-octahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;-   (1R*,7R*,7aR*,12bS*)-11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,7a,8,12b-octahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;-   8-[2-(6-chloropyridin-3-yl)ethyl]-11-methyl-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;-   11-methyl-8-[2-(2-methylphenyl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;-   5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;-   (6R,10S)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;-   (6S,10R)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;-   10-methyl-7-[2-(6-methylpyridin-3-yl)ethyl]-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole;-   10-methyl-7-[2-(2-methylphenyl)ethyl]-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole;-   7-[2-(4-chlorophenyl)ethyl]-10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole;-   (4aR*,9bR*)-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1,4-ethanopyrido[3,2-b]indole;-   (4aR*,9bR*)-7-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1,4-ethanopyrido[3,2-b]indole;-   (4aR*,9bR*)-8-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1,4-ethanopyrido[3,2-b]indole;-   5-[(4-chlorophenyl)sulfonyl]-8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole;-   6-isoquinolin-7-yl-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-quinazolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol;-   6-(4-methoxyquinazolin-6-yl)-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-methyl-6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-isoquinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-quinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-quinazolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(4-methoxyquinazolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol;-   6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-quinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[4-(4-methylpiperazin-1-yl)phenyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   2-[2-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)ethyl]pyridazin-3    (2H)-one;-   1-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridin-2(1H)-one;-   9-fluoro-6-{[6-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-{[6-(piperidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-isopropyl-N-methylpyridin-2-amine;-   N-(1,3-dioxolan-2-ylmethyl)-5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-methylpyridin-2-amine;-   9-fluoro-6-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-(2-methoxyethyl)-N-methylpyridin-2-amine;-   9-fluoro-6-[(5-fluoropyridin-3-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   2-{5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]pyridin-2-yl}pyridazin-3(2H)-one;-   9-fluoro-6-[(2-phenylpyrimidin-5-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(1H-benzimidazol-2-ylmethyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(quinolin-8-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-[(3-methyl-1,2-oxazol-5-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   2-{4-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]phenyl}pyridazin-3(2H)-one;-   6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6′-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,2′-bipyridin-2-one;-   6-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol;-   7-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinoxalin-2(1H)-one;-   7-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one;-   2-[6-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)pyridin-3-yl]pyridazin-3(2H)-one;-   9-fluoro-6-(2-methylpyrimidin-5-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   9-fluoro-6-(pyridin-3-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[6-(morpholin-4-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)nicotinamide;-   6-(1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(quinazolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(isoquinolin-7-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-(isoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6-[4-(1H-imidazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;-   6′-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,2′-bipyridin-2-one;-   7-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinoxalin-2(1H)-one;-   7-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,4-benzoxazin-3(4H)-one;-   2-amino-5-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)benzamide;-   7-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one;-   (7S,10R)-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7S,10R)-11-methyl-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   (7R,10S)-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;-   7-[(7S,10R)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one;-   7-[(7R,10S)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one;-   6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole;-   (7R,10S)-11-methyl-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;    or-   2-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridazin-3(2H)-one.

The present invention also features processes for the preparation of thecompounds of the invention. In one embodiment, the present inventionprovides a process for preparing a compound of formula (VIII) comprisingthe step of reacting a compound of formula (VII) under alkylationconditions, cross-coupling conditions, or nucleophilic aromaticsubstitution conditions, wherein R⁶ is alkyl, —S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)-G¹,—(CR^(4a)R^(5a))_(m)-G²-G¹, —CR^(4a)═CR^(5a)-G¹, -G¹, or -G²-G¹.Compounds of formula (VIII) are representative of compounds of formula(I). The preparation of compounds of formula (VII) and (VIII) aredescribed in the Examples.

In another embodiment, the present invention provides a process forpreparing a compound of formula (X) comprising the step of reacting acompound of formula (IX) under alkylation conditions, cross-couplingconditions, or nucleophilic aromatic substitution conditions, wherein R⁶is alkyl, —S(O)₂R^(2a), —(CR^(4a)R^(5a))_(m)—OR^(1a),—(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G²-G¹,—CR^(4a)═CR^(5a)-G¹, -G¹, or -G²-G¹. Compounds of formula (X) arerepresentative of compounds of formula (IV). Compounds of formula (IX)and (X) are prepared as described in the Examples.

In a another embodiment, the present invention provides a process forpreparing a compound of formula (XII) comprising the step of reacting acompound of formula (XI) under alkylation conditions, cross-couplingconditions, or nucleophilic aromatic substitution conditions, wherein R⁶is alkyl, —S(O)₂R^(2a), —(CR^(4a)R^(5a))_(m)—OR^(1a),—(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G²-G¹,—CR^(4a)═CR^(5a)-G¹, -G¹, or -G²-G¹. Compounds of formula (XII) arerepresentative of compounds of formula (VI). Compounds of formula (XI)and (XII) are prepared as described in the Examples.

Compounds of the present invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30.

On occasion, the relative stereochemistry of an enantiomeric pair isknown, however, the absolute configuration is not known. In thatcircumstance, the relative stereochemistry descriptor terms “R*” and“S*” are used. The terms “R*” and “S*” used herein are defined in Eliel,E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley &Sons, Inc.: New York, 1994; pp 119-120 and 1206.

The present application contemplates various stereoisomers and mixturesthereof and these are specifically included within the scope of thisapplication. Stereoisomers include enantiomers and diastereomers, andmixtures of enantiomers or diastereomers. Individual stereoisomers ofcompounds of the present application may be prepared synthetically fromcommercially available starting materials which contain asymmetric orchiral centers or by preparation of racemic mixtures followed byresolution which is well known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Geometric isomers may exist in the compounds of the present invention.The present invention contemplates the various geometric isomers andmixtures thereof resulting from the disposition of substituents around acarbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkylgroup, or a heterocycle group. Substituents around a carbon-carbondouble bond or a carbon-nitrogen bond are designated as being of Z or Econfiguration and substituents around a cycloalkyl or a heterocycle aredesignated as being of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric or stereoisomeric forms. It is to beunderstood that the present invention encompasses any tautomeric orstereoisomeric form, and mixtures thereof, and is not to be limitedmerely to any one tautomeric or stereoisomeric form utilized within thenaming of the compounds or formulae drawings.

Compounds of this invention can exist in an isotopic form containing oneor more atoms having an atomic mass or mass number different from theatomic mass or mass number most abundantly found in nature. Isotopes ofatoms such as hydrogen, carbon, phosphorous, sulfur fluorine, chlorine,and iodine include, but are not limited to ²H, ³H, ¹¹C, ¹⁴C, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Compounds that contain other isotopesof these and/or other atoms are within the scope of this invention.Compounds containing tritium (³H) and ¹⁴C radioisotopes are preferred ingeneral for their ease in preparation and detectability for radiolabeledcompounds. Isotopically labeled compounds of this invention can beprepared by the general methods well known to persons having ordinaryskill in the art. Such Isotopically labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples and Schemes below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

c. BIOLOGICAL DATA

To determine the effectiveness of compounds having a formula (I), (II),(III), (IV), (V), or (VI), these compounds can be evaluated in in vitromodels of cellular function and in vivo models of pro-cognitive effects.

Abbreviations which have been used in the descriptions of BiologicalData that follow are: DMEM for Dulbecco's modified Eagle's medium; DMSOfor dimethyl sulfoxide; FBS for fetal bovine serum; FLIPR forfluorometric imaging plate reader; GFAP for glial fibrillary acidicprotein; HBSS for Hank's balanced salt solution; i.p. forintraperitoneal; NGF for nerve growth factor; PBS for phosphate bufferedsaline; TMRE for tetramethylrhodamine ethyl ester perchlorate; and TRITCfor tetramethylrhodamine isothiocyanate.

(i) Effects on Neurite Outgrowth in Neurons and Neuronal Cell Lines:

Effects on cellular properties such as neurite outgrowth and neuronal orneuronal-like cell number, etc. can be measured either using rat orhuman neuronal/neuroblastoma cell lines (e.g., SH-SY5Y, PC12, IMR-32,etc.) or using primary cells (e.g., rat cortical neurons). For example,it has been reported that dimebolin can increase neurite outgrowth inprimary rat cortical neurons, comparable to that evoked by Brain DerivedNeurotrophic factor (BDNF) (Hung, D. Dimebon: A phase 3 investigationalagent for Alzheimer's disease with a novel mitochondrial mechanism ofaction. Presented at the International Conference on Alzheimer'sDisease, Chicago, Ill., USA, July 2008; paper S4-04-05.).

For example, studies were conducted using PC12 cells plated in 96-wellplates, treated with or without nerve growth factor (100 ng/mL) for 6days. Compounds were then added at various concentrations (ranging from0.1 nM to 30 μM), and incubated for 24 hours. Cells were then fixed andstained by neuron marker β-tubulin (green), and nuclei were stained byHoechst 33342 (blue). Images were collected using the ImageXpress Microautomatic fluorescent microscopy system (Molecular Devices, Sunnyvale,Calif.) employing a Nikon 10× Plan Fluor objective and Cool Snap HQ CCDcamera. The Neurite Outgrowth module in the MetaMorph Imaging softwarewas used to automatically count neuron-like number, and the extent ofneurite outgrowth (See, FIG. 1).

In addition to PC12 cells, other cellular model systems may also beused. Rat cortical cells were cultured and prepared for high contentmicroscopy analysis as previously described (Hu, M.; Schurdak, M. E.; etal. High content screen microscopy analysis of Aβ₁₋₄₂-induced neuriteoutgrowth reduction in rat primary cortical neurons: Neuroprotectiveeffects of α7 neuronal nicotinic acetylcholine receptor ligands. BrainRes. 2007, 1151, 227-235.). Briefly, cortical cell cultures were platedat density of 5×10⁵ cells/mL onto poly-D-lysine coated 96-well platesand maintained in a cell incubator at 37° C. with 5% CO₂. Experimentswere performed using 6-7 day-old cortical cell cultures by treating withtest compounds. In some experiments, the effect of test compounds onreversing Aβ toxicity were also measured (Hu, M.; Schurdak, M. E.; etal. High content screen microscopy analysis of Aβ₁₋₄₂-induced neuriteoutgrowth reduction in rat primary cortical neurons: Neuroprotectiveeffects of α7 neuronal nicotinic acetylcholine receptor ligands. BrainRes. 2007, 1151, 227-235.). For assessment of neuroprotective effects,cells were first pretreated with test compounds for about 5 hours.Medium was then replaced with the medium containing freshly preparedabout 5 μM Aβ₁₋₄₂ peptide in the absence or presence of the testcompounds for 3 days. The untreated group contained the same percentageof vehicle (DMSO) as in the treatment groups. Cells were fixed withapproximately 4% paraformaldehyde containing 0.5% Hoechst 33342 forabout 15 minutes, followed by three washes using PBS (pH 7.4) andblocked with 10% donkey serum in PBS for 1 hour at room temperature. Thecells were then incubated overnight at about 4° C. with mouseanti-tubulin monoclonal antibody (1:100) for staining neurons and rabbitanti-GFAP (1:1000) for staining glia. In the next day, cells wereincubated with FITC-labeled anti-mouse and TRITC-labeled anti-rabbitantibodies (1:1000) for about 1 hour at room temperature. After fixingand staining the cells, nuclei (360/400 nm excitation and 465/300 nmemission filters), neuron (475/350 nm excitation and 535/400 nm emissionfilters) and glial cell (535 nm excitation and 610 nm emission filters)images were collected using the ImageExpress Micro automatic fluorescentmicroscopy system (Molecular Devices, Sunnyvale, Calif.) employing aNikon 10× Plan Fluor objective and Cool Snap HQ CCD camera. The NeuriteOutgrowth module in the MetaMorph Imaging software was used toautomatically count total cell number, number of neuron cells, and theextent of neurite outgrowth.

As shown in FIG. 2, treatment with Example 5 resulted in significantattenuation of the Aβ₁₋₄₂-induced reduction of neurite outgrowth inprimary postnatal (P0) cortical cells. In the graph of FIG. 2, 100%response was the response observed for untreated cells. Exposure toAβ₁₋₄₂ produced a decrease in neurite outgrowth. Treatment of cells withcompounds prior to and concomitantly with Aβ₁₋₄₂ gave a neuroprotectiveeffect with neurite outgrowth maintained or enhanced relative tountreated cells.

Table 1 shows the maximum response at the noted test compoundconcentration relative to 300 nM dimebolin.

TABLE 1 Neurite Outgrowth Assay Maximum Effect (of % 300 nM ExampleDimebolin) at Concentration (nM) Count 2 117% at 0.03 nM 2 5 123% at3000 nM 3 6 124% at 3 nM 4 31 96% at 30 nM 3 50 101% at 30 nM 3 133 108%at 30 nM 3 135 126% at 3 nM 3 158 110% at 30 nM 3 165 104% at 300 nM 3167 92% at 300 nM 3 228 141% at 300 nM 1 229 165% at 300 nM 1 248 109%at 300 nM 3 261 104% at 30 nM 2 262 99% at 3 nM 2 264 110% at 300 nM 2274 111% at 300 nM 2 277 91% at 300 nM 2 278 96% at 0.003 nM 3 279 108%at 3 nM 3 280 107% at 300 nM 3 282 115% at 30 nM 3(ii) Effects on Aβ₁₋₄₂ Induced Tau Phosphorylation in PC12 Cells

The effect of test compound(s) on Aβ₁₋₄₂ induced tau phosphorylation canbe assessed in a cell line such as PC12 as previously described (Hu, M.;Waring, J. F.; et al. Role of GSK-3β activation and α7 nAChRs inAβ₁₋₄₂-induced tau phosphorylation in PC12 cells. J. Neurochem. 2008,106(3), 1371-1377.). Briefly, PC12 cells are plated on poly-D-lysinecoated 96-well plates, cultured in Ham's F12K medium supplemented with15% horse serum, 2.5% FBS, 2 mM L-glutamine, 100 U/mL penicillin and 100μg/mL streptomycin at 37° C. with 5% CO₂ and differentiated with 100ng/mL NGF for approximately 6 days. Cells are pretreated with testcompounds for 30 minutes at about 37° C. The medium is then replacedwith that containing freshly prepared Aβ₁₋₄₂ or control peptide in theabsence or presence of the test compounds and the cells are incubated at37° C. for 24 hours. Cells are fixed with 3.7% formaldehyde in PBS (pH7.4) for about 1 hour at room temperature followed by permeabilizationby three washes with 0.1% Triton-X 100 in PBS. The fixed cells areincubated with blocking buffer for about 2 hours at room temperaturefollowed by overnight incubation with primary antibodies AT8 (forphosphorylated tau), anti-human tau (for total Tau), or anti-GSK-3β. Onthe next day, cells are washed 3 times with 0.1% Tween-20 in PBS, thenincubated with IRDye® 800CW anti-mouse IgG antibodies (1:100) for 1 hourat room temperature for detection of phosphorylated tau (p-tau) orGSK-3β, or with the Alexa Fluor® 680 anti-rabbit antibodies (1:100) fordetection of total tau (t-tau). Cells are then washed three times, andthe target signals are simultaneously visualized using Odyssey InfraredImaging Scanner with the 680-nm fluorophore emitting an image of redcolor and the 800-nm fluorophore emitting an image of green color. Theintegrated fluorescence intensities are calculated and analyzed usingthe Odyssey Infrared Imaging System Application Software version 1.2.15(Li-Cor Biosciences (Lincoln, Nebr.). The p-tau and t-tau levels aretypically presented as the ratio p-tau/t-tau (Hu, M.; Waring, J. F.; etal. Role of GSK-3β activation and α7 nAChRs in Aβ₁₋₄₂-induced tauphosphorylation in PC12 cells. J. Neurochem. 2008, 106(3), 1371-1377.).

(iii) Effects on Mitochondrial Function

The method also involves a high-throughput assay using serum-deprivationconditions involving neuronal cells to screen for compounds thatincrease or preserve mitochondrial membrane potential. Such compoundscan be found to aid in rescuing cells from energy-depletion that occursin several neurodegenerative states. Mitochondrial-mediated apoptosisoccurs in response to a wide range of apoptotic stimuli including p53,c-myc, DNA damage, prooxidants, chemotherapeutic agents, serumstarvation and death receptor activation (Lin C-H., Lu Y-Z., Cheng,F-C., Chu L-F. and Hsueh C-M. Bax-regulated mitochondrial-mediatedapoptosis is responsible for the in vitro ischemia induced neuronal celldeath of Sprague Dawley rat. Neuroscience Lett. 2005, 387, 22-27).

Serum deprivation for 16-18 hours initiates the early stages ofapoptosis (Chavier D, Lecoeur H, Langonne A, Borgne-Sanchez A, MarianiJ., Martinou J-C, Rebouillat D and Jacotot E. Upstream control ofapoptosis by caspase-2 in serum-deprived neurons. Apoptosis10:1243-1259, 2005) and induces stress on a cell before full commitmentto cell death. Mitochondria play a critical role in the cell forsurvival or death due to their regulation of both energy metabolism aswell as apoptosis (Sullivan P G, Rabchevsky A G, Waldmeirer P C andSpringer J E. Mitochondrial Permeability Transition in CNS Trauma: Causeor Effect of Neuronal Cell Death. J. Neuroscience Res. 2005, 79,231-239). One of the first major events to occur in apoptosis is thebreakdown of the membranes of the mitochondria to release cytochrome c,activate caspases, change electron transport and cause a decrease inmitochondrial membrane potential (Δψ_(m)). A change in Δψ_(m) thereforeserves as a measure of mitochondrial function and indicator of cellhealth.

Thus, this stress inducer, serum deprivation, combined with monitoringchanges in the mitochondrial membrane potential in a 96-well formatallows for the establishment of an efficient high-throughput screen(HTS) in order to evaluate the ability of compounds to increasemitochondrial membrane potential in the presence of stress and preservehealth of the cell. Exemplary procedures for conducting suchhigh-throughput assay are provided below.

Tissue Culture:

SK-N-SH human neuroblastoma cells obtained from American Type CultureCollection (Rockville, Md.) were maintained in the log phase of growthin Minimal Essential Media (MEM), 10% heat inactivated fetal calf serumand 100 units/mL antibiotic-antimycotic (AA). Cells were cultured andmaintained in a humidified incubator at 37° C. under 5% CO₂ and 95% air.Cells were trypsinized (0.25%) and subcultured every 3 days and usedfrom 15-18 passages. All cell culture supplies were obtained fromInvitrogen (Carlsbad, Calif.).

Serum Deprivation/JC-1 Mitochondrial Membrane Potential (MMP) Assay.

SK-N-SH cells were plated 2-3 days in advance at a concentration of50,000 cells/well onto collagen coated black-walled 96 well plates(Becton-Dickinson, Bedford, Mass.) in a total volume of 200 μL. On dayof experimental treatment, the media containing serum was aspirated fromeach well and rinsed once with MEM/1% AA without serum. The cells thenwere incubated overnight in 100 μL of MEM/1% AA (no serum) with andwithout dimebolin or novel chemical entities overnight for ˜18 hours.The following day, JC-1 dye(5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanide) wasdiluted 1:10 into MEM media according to the JC-1 Mitochondrial MembranePotential Assay Kit: (Cayman Chemical Company, Ann Arbor, Mich.) andthen 10 μL of the JC-1 dye solution was added to each well. The plateswere centrifuged for 5 minutes at 400×g at room temperature followed by35 minute incubation at 37° C. The plates were washed twice with 200□ μLof provided Assay Buffer followed an addition of 100 μL of Assay Bufferto each well. The plates were read with an excitation and emission of560 nM and 595 nM for red fluorescence and with an excitation andemission of 485 nM and 535 nM for green fluorescence to determine thefinal JC-1 value taking the red to green fluorescence ratio. This assayis based on change in mitochondrial membrane potential (MMP) using thislipophilic cationic dye, JC-1, by monitoring the changes in the ratio ofred to green fluorescence as the MMP depolarizes. This change in MMPreflects the health of the cell with healthy, viable cells have a highJC-1 ratio and high MMP whereas apoptotic, unhealthy cells have a lowJC-1 ratio or low MMP.

For the ability of compounds to reverse the stress due to serumdeprivation and increase the JC-1 ratio, the percent maximal intensityin JC-1 ratio was normalized to that induced by the peak value for 10 μMdimebolin and plotted against the compound concentration to calculateEC₅₀ values and to control for plate-to-plate variability.Concentration-response data were analyzed using GraphPad Prism (SanDiego, Calif.); the EC₅₀ values were derived from a single curve fit tothe mean data of n=2-3, in duplicates. Selected data is shown in Table2.

All compounds were dissolved in dimethyl sulfoxide at 10 mM stocksolutions and tested at a concentration that the dimethyl sulfoxidelevels never exceeded 1%.

As shown in FIG. 3, treatment of SK-N-SH cells with Example 5 maintainedmitochondrial function in a dose dependent manner.

TABLE 2 JC-1 Mitochondrial Membrane Potential (MMP) Assay Example EC₅₀(μM) JC-1 max % 3 5.11 191 5 12.98 209 6 5.79 163 12 5.58 181 14 4.79110 16 8.38 129 17 3.53 345 18 3.19 307 23 3.32 332 24 2.26 221 31 6.0597 32 17.32 53 33 5.81 97 34 18.09 175 35 6.71 78 43 7.64 202 44 3.31291 50 6.45 175 59 4.14 202 61 4.37 211 67 6.49 132 68 3.22 213 69 4.43161 77 9.22 223 78 9.69 211 84 6.76 173 87 3.33 139 90 3.43 176 91 6.33129 93 4.81 186 96 4.41 169 97 5.13 164 98 7.26 176 99 3.07 138 100 3.63140 103 4.17 180 104 4.16 178 105 3.88 129 106 5.73 238 107 4.08 153 1123.43 101 113 2.99 353 120 3.40 197 121 3.63 129 122 5.29 141 127 3.69151 140 3.32 194 146 2.84 264 147 2.53 266 148 3.52 99 150 3.60 134 1515.38 121 152 3.86 156 154 30.00 31 155 7.53 63 159 2.67 240 160 1.61 194162 16.97 205 163 4.03 140 164 4.95 197 167 4.71 149 173 6.15 120 1745.48 105 178 4.17 192 179 5.69 116 181 7.89 103 182 9.28 60 183 8.97 172184 10.70 175 185 8.58 184 186 14.57 93 187 9.37 110 188 6.52 96 18911.35 107 190 5.06 175 191 7.04 112 194 2.18 321 196 3.91 182 197 5.63173 202 3.07 239 203 4.53 159 204 3.23 182 213 5.43 177 215 3.34 196 2164.20 284 217 2.94 182 219 3.07 201 222 4.43 215 223 3.84 287 224 3.17215 225 2.74 209 226 1.68 307 227 3.62 266 228 1.73 263 229 0.70 282 2320.81 220 233 0.80 250 234 1.27 281 235 3.96 252 236 1.74 268 237 2.48174 238 11.55 86.53 240 3.33 170 241 7.96 156 242 8.12 169 243 8.36 169244 5.65 226 245 10.02 189 246 8.76 148 247 4.65 192 248 5.24 110 2495.27 133 250 8.37 77.35 251 4.39 193 252 6.2 109 253 4.4 185 254 8.0957.12 255 5.72 171 256 15.47 89.6 257 3.6 155 258 2.99 149 259 3.2 126260 2.91 191 261 5.72 160 262 8.71 182 263 11.01 108 264 7.8 107 2651.84 264 266 10.74 127 267 9.72 70.03 268 4.43 237 269 0.745 204 2702.81 270 271 3.17 264 272 3.99 149 273 7.48 190 274 2.27 235 275 3.44130 276 6.65 80.55 277 2.4 190 278 2.71 189 279 5.49 209 280 5.25 201281 1.74 228 282 3.21 228 283 6.02 170 284 7.62 108 285 9.41 149 2864.41 239 287 1.53 209(iv) In Vivo Models of Procognitive Effects

A range of animal models capturing diverse cognitive domains may beutilized for assessing procognitive effects of compounds. Examples ofthese models are provided in Bitner et al., (Bitner, R. S.; Bunnelle, W.H.; et al. Broad-spectrum efficacy across cognitive domains by α7nicotinic acetylcholine receptor agonism correlates with activation ofERK1/2 and CREB phosphorylation pathways. J. Neurosci. 2007, 27(39),10578-10587.). Various transgenic animal models that are relevant ofneurodegenerative diseases of interest may also be utilized to assesseffects of test compounds (Goetz, J.; Ittner, L. M. Animal models ofAlzheimer's disease and frontotemporal dementia. Nat. Rev. Neurosci.2008, 9(7), 532-544.).

Inhibitory Avoidance in Mouse: The inhibitory avoidance task involvesthe uses of a two-compartment step through apparatus (Ugo Basile,Collegeville, Pa.) that measures the animal's ability to remember abrief noxious stimulus (foot shock), and is considered a measure oftrial learning, and memory consolidation. Briefly, mice were placed in alighted compartment of the apparatus where the latency to enter into thepreferred dark compartment is recorded. Entry into a dark compartmentresulted in the immediate delivery of a mild foot shock (0.2 mA,1-second duration). Retention testing was conducted 24 hours later withthe animal again placed in the lighted compartment where its latency toreenter the dark side of the apparatus was measured (no shock).Increasing retention latency was regarded as an index of memoryconsolidation (Bitner, R. S.; Bunnelle, W. H.; et al. Broad-spectrumefficacy across cognitive domains by α7 nicotinic acetylcholine receptoragonism correlates with activation of ERK1/2 and CREB phosphorylationpathways. J. Neurosci. 2007, 27(39), 10578-10587.). As shown in FIG. 4,the latency to reenter the dark side (punishment side) was significantlyincreased upon dosing with Example 5 at 0.11 mg/kg and 1.1 mg/kg.

Social Recognition in Rat: The social recognition test measuresshort-term memory on the basis of olfactory cues, and depends on thehippocampus. Adult (350-450 g) rats were allowed to interact with ajuvenile (60-80 g) rat for a 5 minute interaction trial (T1) in whichthe adult exhibits behaviors that included close following, groomingand/or sniffing of the juvenile for as much as 40-50% of the trialduration. The juvenile rat was then removed and the adult ratimmediately administered various doses of test compound. A second 5minute recognition trial (T2) was conducted 120 minutes later whereinteractive behavior of the adult rat was again monitored. Ifrecognition memory was lost over the 120 minute interval between trials,the interactive behavior would be similar for the two trials; however,if memory was retained, the recognition ratio (T2:T1) would decline,i.e. decreasing T2:T1 ratio was regarded as an index of improvedshort-term recognition memory (Bitner, R. S.; Bunnelle, W. H.; et al.Broad-spectrum efficacy across cognitive domains by α7 nicotinicacetylcholine receptor agonism correlates with activation of ERK1/2 andCREB phosphorylation pathways. J. Neurosci. 2007, 27(39), 10578-10587.Timmermann, D. B.; Groenlien, J. H.; et al. An allosteric modulator ofthe α7 nicotinic acetylcholine receptor possessing cognition-enhancingproperties in vivo. J. Pharmacol. Exp. Ther. 2007, 323(1), 294-307.). Asshown in FIG. 5, the recognition ratio (T2:T1) declined significantlyupon dosing intraperitoneally with Example 5 at 0.11 and 1.1 mg/kg.

Delayed Matching-to-Sample (DMTS) Titration in Monkey: Studies can beconducted in Rhesus monkeys that were initially trained in the DMTSprocedure (Buccafusco, J. J.; Terry, A. V.; et al. Profile of nicotinicacetylcholine receptor agonists ABT-594 and A-582941, with differentialsubtype selectivity, on delayed matching accuracy by young monkeys.Biochem. Pharmacol. 2007, 74(8), 1202-1211.). Using a touch-sensitivescreen in the animals home-cage, trial initiation consists ofpresentation of one of three colored stimuli (red, blue, or yellowrectangles) that remain in view (sample stimuli) until touched bysubject. Following a delay interval, two choice rectangles arepresented, one being the previous sample stimulus, in which correct(matching) choice-touch to the sample stimuli is food reinforced. Forstandard DMTS testing, the duration for each delay interval is adjustedfor each subject until three levels of performance accuracy wereapproximated: zero delay (85-100% of trials answered correctly); shortdelay interval (75-84% correct); medium delay interval (65-74% correct);and long delay interval (55-64% correct). The titration version of theDMTS task used in the present studies requires the animals to perform a96 trial session that begins with a 0 sec delay interval. If the trialis answered correctly, a 1 second delay interval is presented during thenext trial presented. The 1 second incremental progression is maintaineduntil the subject made an incorrect match. The delay interval for thetrial after an incorrect match is always decreased by 1 second. After anincorrect match, if the next trial is answered correctly, then thesubsequent trial presented a delay interval 1 second longer in duration.Dependent variables include the overall % of trials answered correctly,the number of trials to reach the maximal delay interval attained, andthe maximum and average delay interval attained (in seconds). Compoundsare administered prior to DMTS testing.

(v) Determination of Analgesic Effect Against Neuropathic Pain

Animals were prepared for testing, by use of a surgical procedure thatinduces neuropathic pain in one paw. Male Sprague Dawley rats werepurchased from Charles River (Portage, Mich.). Prior to surgery, animalswere housed in groups and maintained in a temperature-regulatedenvironment. Following nerve ligation surgery, animals were housed ingroups, and had access to food and water ad libitum.

The L5 and L6 spinal nerves of anesthetized rats were tightly ligated ina manner described previously (see Kim and Chung, Pain (1992) vol. 50pp. 355-363). An incision was made on the dorsal portion of the hip andthe muscle was blunt-dissected to reveal the spinal processes. The L6transverse process was removed, and the left side L5 and L6 spinalnerves were tightly ligated with 5.0 braided silk suture. The wound wascleaned, the membrane sewn with 4.0 dissolvable Vicryl suture and theskin closed with wound clips. The paw affected by the surgical procedure(the left paw) develops an allodynic response, a hypersensitivity tomechanical and other stimuli; neuropathic pain is assessed as anincreased sensitivity in the surgically affected (left) allodynic pawcompared to the control paw on the right side, and measured by comparingthe response of the (left side) allodynic paw to the response of theunaffected right side control paw.

For the assessment of neuropathic pain, mechanical allodynia in theaffected paw of animals that had undergone spinal nerve ligation wasevaluated using testing with von Frey filaments. As described previouslyby S. R. Chaplan, et al (“Quantitative assessment of tactile allodyniain the rat paw” J. Neurosci. Meth. (1994) vol. 53 pp. 55-63), two weeksfollowing surgery rats were acclimated to a testing box constructed ofplexiglass with a wire mesh floor which allowed access to the plantarsurface of the animal's hindpaws. Using an Up-Down method (Dixon, AnnualRev. Pharmacol. Toxicol. (1980) vol. 20, pp. 441-462; Chaplan et al.“Quantitative assessment of tactile allodynia in the rat paw” J.Neuroscience Methods (1994) vol. 53 pp. 55-63), von Frey filaments ofincreasing stiffness were applied to the plantar surface of the hindpawsand the withdrawal response of the animals was observed; for thesurgically affected paw with neuropathic pain (the left side paw) thebaseline level of allodynia has a withdrawal threshold of <4 g ofpressure. By comparison, for the control paw without allodynia (in thiscase the right side paw), the typical withdrawal pressure is around 15g. Representative compounds of the invention, administeredintraperitoneally 30 minutes before testing, were able to reduce thesymptoms of neuropathic pain and induce a dose-dependent increase in thewithdrawal threshold for allodynic (left side) limb, up to a maximumeffect of 15 g. The efficacy of the compound in reducing neuropathicpain at different doses was determined by comparing response in thesurgery-affected paw versus the response in the control paw. This wasexpressed as the MPE (maximum potential effect). In this model, thecompound of Example 2(9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole)was very effective, producing a 58% reduction (**p<0.01, ***p<0.001 vs.vehicle) in the withdrawal threshold at a dose of 10 mg/kg, administeredby intraperitoneal injection as shown in FIG. 6. Example 2 was dosedi.p. (1, 3, and 10 mg/kg, 2 mL/kg) in vehicle (10% dimethylsulfoxide/HBC). Gabapentin (100 mg/kg, 2.0 mL/kg) was used as aninternal control. Test animals were used 2.5 weeks post-surgery. Nocomplicating adverse effects were observed.

(vi) Animal Pharmacokinetics

The pharmacokinetic properties of test compounds were assessed in mouse,rat, dog and monkey to obtain various parameters including clearance(Clp), volume of distribution and bioavailability. For the determinationof plasma and brain concentrations of the parent compound, naïve rats ormice can be dosed with the compounds i.p. and sacrificed at various timepoints post-dosing. For the determination of plasma concentrations,blood was collected into heparinized tubes and then centrifuged, and theseparated plasma is frozen at −20° C. until analysis. For analysis,compounds were extracted from the samples via liquid-liquid extractionand quantified by liquid chromatography/mass spectroscopy.

d. METHODS OF USING THE COMPOUNDS

In still yet another embodiment, the present invention provides a methodfor preventing or treating a disease condition in a subject in need oftreatment thereof. The subject in need of treatment thereof can be amammal, such as, but not limited to, a human.

In one aspect, the disease condition is a neurodegeneration disorder. Aneurodegeneration disorder refers to a type of neurological diseasemarked by the loss of nerve cells in the brain or central nervoussystem. Examples of neurodegeneration disorders include, but are notlimited to, Alzheimer's disease (AD), mild cognitive impairment (MCI),age-associated memory impairment (AAMI), multiple sclerosis, Parkinson'sdisease, vascular dementia, senile dementia, AIDS dementia, Pick'sdisease, dementia caused by cerebrovascular disorders, corticobasaldegeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease,diminished CNS function associated with traumatic brain injury or anycombinations thereof.

In another aspect, the disease condition is a neuropsychiatric disorder.A neuropsychiatric disorder is a behavioral or psychological problemassociated with a known neurological condition, and typically defined asa cluster of symptoms that co-exist. Examples of neuropsychiatricdisorders include, but are not limited to, schizophrenia, cognitivedeficits in schizophrenia, attention deficit disorder, attention deficithyperactivity disorder, bipolar and manic disorders, depression or anycombinations thereof.

In a further aspect, the present invention relates to methods ofpreventing or treating a pain including neuropathic and nociceptivepain, chronic or acute, such as, without limitation, allodynia,inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns,back pain, ocular pain, visceral pain, cancer pain, dental pain,headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis,sciatica, pelvic hypersensitivity, pelvic pain, post operative pain,post stroke pain, and menstrual pain.

Cognitive deficits are recognized in various forms of neurodegenerationand neuropsychiatric disorders (such as, but not limited to, dementia,including Alzheimer's disease, (AD) and neuropsychiatric diseases,particularly schizophrenia and bipolar disorders). For example, in AD,current therapies offer modest efficacy, and therefore, there is needfor an agent that offers a superior clinical benefit. One such agent,dimebolin, has been shown to inhibit neuronal death in models ofneurodegenerative diseases suggestive of modification of diseaseprocesses (Lermontova, N. N.; Lukoyanov, N. V.; et al. Dimebon improveslearning in animals with experimental Alzheimer's disease. Bull. Exp.Biol. Med. 2000, 129(6), 544-546. Bachurin, S.; Bukatina, E.; et al.Antihistamine agent dimebon as a novel neuroprotector and a cognitionenhancer. Ann. N. Y. Acad. Sci. 2001, 939 (Neuroprotective Agents),425-435) and more recently, shown to possess beneficial effect incognition in patients with Alzheimer's disease (Burns, A.; Jacoby, R.Dimebon in Alzheimer's disease: old drug for new indication. Lancet2008, 372(9634), 179-80. Doody, R. S.; Gavrilova, S. I.; et al. Effectof dimebon on cognition, activities of daily living, behaviour, andglobal function in patients with mild-to-moderate Alzheimer's disease: arandomised, double-blind, placebo-controlled study. Lancet 2008,372(9634), 207-215.). Patients with mild-to-moderate Alzheimer's diseaseadministered with 20 mg three times a day (60 mg/day) showed significantimprovement in the clinical course of disease, as reflected inimprovement over baseline for ADAS-Cog (Alzheimer's disease assessmentscale—cognitive subscale) (Cummings, J.; Doody, R.; Gavrilova, S.; Sano,M.; Aisen, P.; Seely, L.; Hung, D. 18-month data from an open-labelextension of a one-year controlled trial of dimebon in patients withmild-to-moderate Alzheimer's disease. Presented at the InternationalConference on Alzheimer's Disease (ICAD), Chicago, Ill., USA, July 2008;paper P4-334). Patients with mild-to-moderate Alzheimer's disease whohad earlier received the drug for 12 months had preservation of functionclose to their starting baseline on key symptoms of Alzheimer's diseaseindicated the ability of dimebolin to alter disease progression.Patients originally on placebo who received dimebolin in the extensionstudy showed stabilization across all key measures.

Beneficial effects of agents such as dimebolin have been linked todiverse mechanisms of action including effects at the level ofmitochondria. In particular, dimebolin has been reported to improveneuronal function by enhancing neuronal outgrowth and affectingmitochondrial function. For example, Hung and coworkers (Hung, D.Dimebon: A phase 3 investigational agent for Alzheimer's disease with anovel mitochondrial mechanism of action. Presented at the InternationalConference on Alzheimer's Disease, Chicago, Ill., USA, July 2008; paperS4-04-05) reported that dimebolin can protect cells from excitotoxicdamage and improve neurite outgrowth in in vitro model systems. Othermechanisms of action may also contribute to its beneficial effects ofcompounds with a “dimebolin-like” profile. Indeed, multi-targetedmechanisms have been proposed as viable approaches for treatment ofdiverse neurodegenerative diseases (Zhang, H.-Y.One-compound-multiple-targets strategy to combat Alzheimer's disease.FEBS Lett. 2005, 579, 5260-5264. Youdim, M.; Buccafusco, J.Multi-functional drugs for various CNS targets in the treatment ofneurodegenerative disorders. Trends in Pharm. Sci. 2005, 26(1), 27-35.Csermely, P.; Agoston, V.; Pongor, S. The efficiency of multi-targetdrugs: the network approach might help drug design. Trends in Pharm.Sci. 2005, 26(4), 178-182. Cavalli, A.; Bolognesi, M. L.; Minarini, A.;Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-targetdirected ligands to combat neurodegenerative diseases. J. Med. Chem.2008, 51(3), 347-372.). Dimebolin is also thought to exert its cognitiveenhancing effects also through inhibition of butyryl-cholinesterase,acetyl cholinesterase, NMDA receptor or L-type calcium channels(Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebon as anovel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci.2001, 939 (Neuroprotective Agents), 425-435. Lermontova, N. N.;Redkozubov, A. E.; et al. Dimebon and tacrine inhibit neurotoxic actionof beta-amyloid in culture and block L-type Ca(2+) channels. Bull. Exp.Biol. Med. 2001, 132(5), 1079-1083. Grigor'ev, V. V.; Dranyi, O. A.; etal. Comparative Study of Action Mechanisms of Dimebon and Memantine onAMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons.Bull. Exp. Biol. Med. 2003, 136(5): 474-477.). Interactions at the levelof select 5HT receptors have also been implicated in the beneficialcognitive of dimebolin-like analogs (Tkachenko, S. Discovery and in vivoevaluation of potent 5-HT6 receptor antagonists for cognitionenhancement in treating Alzheimer's disease. Presented at theInternational Conference on Alzheimer's Disease (ICAD), Chicago, Ill.,USA, July 2008; paper P2-478.). Thus, available preclinical and clinicaldata suggests that compounds exhibiting a “dimebolin-like” profile canbe beneficial in treating neurodegenerative diseases such as Alzheimer'sdisease and other dementias. Therefore, it is believed that thecompounds of the present invention exhibit at least one of themechanisms of action exhibited by dimebolin.

For treating a neurodegenerative or a neuropsychiatric disorder, themethod comprises administering to the subject in need of treatmentthereof (e.g., a mammal, such as a human) a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof. Alternatively, the methodcomprises administering to the subject a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of at least one cognitive enhancingdrug. A “cognitive enhancing drug”, as defined herein, is a drug thatimproves impaired human cognitive abilities of the brain (namely,thinking, learning, and memory). Cognitive enhancing drugs work byaltering the availability of neurochemicals (e.g., neurotransmitters,enzymes, and hormones), by improving oxygen supply, by stimulating nervegrowth, or by inhibiting nerve damage. Examples of cognitive enhancingdrugs include a compound that increases the activity of acetylcholinesuch as, but not limited to, an acetylcholine receptor agonist (e.g., anicotinic α-7 receptor agonist or allosteric modulator, an α4β2nicotinic receptor agonist or allosteric modulators), anacetylcholinesterase inhibitor (e.g., donepezil, rivastigmine, andgalantamine), a butyrylcholinesterase inhibitor, an N-methyl-D-aspartate(NMDA) receptor antagonist (e.g., memantine), an activity-dependentneuroprotective protein (ADNP) agonist, a serotonin 5-HT1A receptoragonist (e.g., xaliproden), a 5-HT4 receptor agonist, a 5-HT6 receptorantagonist, a serotonin 1A receptor antagonist, a histamine H3 receptorantagonist, a calpain inhibitor, a vascular endothelial growth factor(VEGF) protein or agonist, a trophic growth factor, an anti-apoptoticcompound, an AMPA-type glutamate receptor activator, a L-type or N-typecalcium channel blocker or modulator, a potassium channel blocker, ahypoxia inducible factor (HIF) activator, a HIF prolyl 4-hydroxylaseinhibitor, an anti-inflammatory agent, an inhibitor of amyloid Aβpeptide or amyloid plaque, an inhibitor of tau hyperphosphorylation, aphosphodiesterase 5 inhibitor (e.g., tadalafil, sildenafil), aphosphodiesterase 4 inhibitor, a monoamine oxidase inhibitor, orpharmaceutically acceptable salt thereof. Specific examples of suchcognitive enhancing drugs include, but are not limited to,cholinesterase inhibitors such as donepezil (Aricept®), rivastigmine(Exelon®), galanthamine (Reminyl®), N-methyl-D-aspartate antagonistssuch as memantine (Namenda®). At least one cognitive enhancing drug canbe administered simultaneously with the compounds of the presentinvention or sequentially with the compounds of the present invention(and in any order). Additionally, it is believed that the combinationsdescribed herein may have additive or synergistic effects when used inthe above-described treatment.

In still yet another embodiment, the present invention relates to amethod for preventing (the development of) a disease condition, such asa neurodegeneration disorder or a neuropsychiatric disorder. As usedherein, the term “prevent” a disease condition, such as aneurodegenerative disorder or a neuropsychiatric disorder byadministration of any of the compounds described herein means that thedetectable physical characteristics or symptoms of the disease orcondition do not develop following the administration of the compounddescribed herein. Specifically, the method of the present inventioncomprises administering to the subject in need of treatment thereof(e.g., a mammal, such as a human) a therapeutically effective amount ofany of the compounds as described herein, or a pharmaceuticallyacceptable salt thereof. Alternatively, the method comprisesadministering to the subject a therapeutically effective amount of anyof the compounds as described herein, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofat least one cognitive enhancing drug.

In still yet another embodiment, the present invention relates to amethod for preventing the progression (e.g., worsening) of a diseasecondition, such as a neurodegeneration disorder or a neuropsychiatricdisorder. The method comprises administering to the subject in need oftreatment thereof (e.g., a mammal, such as a human) a therapeuticallyeffective amount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof. Alternatively, the methodcomprises administering to the subject a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of at least one cognitive enhancingdrug.

In the above described methods for preventing the development orprogression of a neurodegeneration disorder or a neuropsychiatricdisorder one or more biomarkers, diagnostic tests or combination ofbiomarkers and diagnostic tests known to those skilled the art can beused to determine whether or not (1) a subject is at risk of developingone or more of neurodegeneration disorders or neuropsychiatricdisorders; or (2) the neurodegeneration disorders or neuropsychiatricdisorders in the subject previously diagnosed with one or more of theaforementioned disorders is progressing (e.g., worsening).

One or more biomarkers, diagnostic tests or combinations of biomarkersand diagnostic tests known in the art can be used to identify subjectswho are at risk of developing a neurodegeneration disorder or aneuropsychiatric disorder. Likewise, one or more biomarkers, diagnostictests or combinations of biomarkers and diagnostic tests known in theart can be used to determine the progression of the disease or conditionof subjects who have been identified as suffering from aneurodegeneration disorder or a neuropsychiatric disorder. For example,one or more biological markers, neuroimaging markers or combination ofbiological or neuroimaging markers (e.g., MRI, etc.) can be used toidentify subjects at risk of developing AD or, for those subjectsidentified as suffering AD, the progression of the disease. Biologicalmarkers that can be examined include, but are not limited to,beta-amyloid₁₋₄₂, tau, phosphorylated tau (ptau), plasma Aβ antibodies,α-antichymotrypsin, amyloid precursor protein, APP isoform ratio inplatelets, β-secretase (also known as BACE), CD59,8-hydroxy-deoxyguanine, glutamine synthetase, glial fibrillary acidicprotein (GFAP), antibodies to GFAP, interleukin-6-receptor complex,kallikrein, melanotransferrin, neurofilament proteins, nitrotyrosine,oxysterols, sulphatides, synaptic markers, S100β, NPS, plasma signalingproteins, etc., or any combinations thereof (See, Shaw, L., et al.,Nature Reviews 2007, 6, 295-303. Borroni, B., et al., Current Med. Chem.2007, 14, 1171-1178. Phillips, K., et al., Nature Reviews 2006, 5463-469. Bouwman, F. H., et al., Neurology 2007, 69, 1006-1011; Ray, S.,et al., Nature Medicine 2007, 13(11), 1359-1362. Cummings, J., et al.,Neurology 2007, 69, 1622-1634.).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of the present invention can be varied so as to obtain anamount of the active compound(s) that is effective to achieve thedesired therapeutic response for a particular subject (e.g., a mammal,preferably, a human (patient)), compositions and mode of administration.The selected dosage level will depend upon the activity of theparticular compound, the route of administration, the severity of thecondition being treated and the condition and prior medical history ofthe patient being treated. However, it is within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

Compounds of the present invention can also be administered to a subjectas a pharmaceutical composition comprising the compounds of interest incombination with at least one pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of the presentinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa subject (namely, a mammal, such as a human) ranges from about 0.01mg/kg body weight to about 100 mg/kg body weight. More preferable dosescan be in the range of from about 0.01 mg/kg body weight to about 30mg/kg body weight. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration. Consequently, singledose compositions may contain such amounts or submultiples thereof tomake up the daily dose.

e. PHARMACEUTICAL COMPOSITIONS

In yet another embodiment, the present invention provides pharmaceuticalcompositions. The pharmaceutical compositions of the present inventioncomprise the compounds of the present invention or a pharmaceuticallyacceptable salt or solvate thereof. The pharmaceutical compositions ofthe present invention comprise compounds of the present invention thatcan be formulated together with at least one non-toxic pharmaceuticallyacceptable carrier.

In yet another embodiment, the present invention provides apharmaceutical composition comprising compounds of the presentinvention, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers, alone or in combination withone or more compounds that are not the compounds of the presentinvention. Examples of one or more compounds that can be combined withthe compounds of the present invention in pharmaceutical compositions,include, but are not limited to, one or more cognitive enhancing drugs.

The pharmaceutical compositions of this present invention can beadministered to a subject (e.g., a mammal, such as a human) orally,rectally, parenterally, intracistemally, intravaginally,intraperitoneally, topically (as by powders, ointments or drops),bucally or as an oral or nasal spray. The term “parenterally” as usedherein, refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of the present invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of the presentinvention include powders, sprays, ointments and inhalants. The activecompound may be mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellantswhich may be required. Ophthalmic formulations, eye ointments, powdersand solutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq.). Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

Esters can be prepared from substrates of formula (I), (II), (III),(IV), (V) or (VI) containing either a hydroxyl group or a carboxy groupby general methods known to persons skilled in the art. The typicalreactions of these compounds are substitutions replacing one of theheteroatoms by another atom, for example:

Amides can be prepared from substrates of formula (I), (II), (III),(IV), (V) or (VI) containing either an amino group or a carboxy group insimilar fashion. Esters can also react with amines or ammonia to formamides.

Another way to make amides from compounds of formula (I) is to heatcarboxylic acids and amines together.

The present invention also contemplates compounds of the presentinvention formed by synthetic means or formed by in vivobiotransformation of a prodrug.

The compounds of the present invention can exist in unsolvated as wellas solvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

f. SCREENING METHODS

In yet another embodiment, the present invention relates to methods foridentifying one or more target compounds that can be used to prevent ortreat a neurodegenerative disorder or a neuropsychiatric disorder in asubject in need of treatment thereof. Preferably, the methods of thepresent invention allow for the identification of one or more targetcompounds in a high throughput manner.

The method of the present invention involves providing a population ofneuronal or neuroblastoma cells or neuronal or neuroblastoma cell lines.Examples of neuronal or neuroblastoma cells or cell lines that can beused in this method include, but are not limited to, PC12, SH-SY5Y,SK-N-SH, IMR-32, or dissociated cells from tissues such as neonatal ratcortex or hippocampus cells. One or more target compounds are added tothe population of neuronal or neuroblastoma cells or cell lines. If morethen one target compound is being added, the target compounds can all bethe same compounds but added in varying concentrations (such as, forexample, 0.1 nM to 30 micromolar). Alternatively, the target compoundscan all be different compounds. After addition of one or more targetcompounds to the population of cells or cell lines described above, thecells or cell lines are allowed to incubate for a period from at leastone 1 hour to about 72 hours, preferably about 24 hours. The neuronalnumber and neurite outgrowth can then be determined using routinetechniques known in the art. For example, the cells or cell lines can befixed and then stained using any stain known in the art, such as, forexample, β-tubulin (green). The total cell number and the extent ofneurite outgrowth can be determined using the Neurite Outgrowth modulein the MetaMorph Imaging software (Commercially available from MolecularDevices, Sunnyvale, Calif.). Target compounds that cause an increase inneuronal number and/or neuronal outgrowth are selected for furthertesting for use in preventing or treating a neurodegenerative orneuropsychiatric disorders.

Method details are described above in the Biological Data section in thedescription of the Effects on Mitochondrial Function assay.

One advantage of the assay is that after a 16-18 hours stress of serumdeprivation, the health of the mitochondria can be measure by a 30minute step with a fluorescent dye, JC-1. JC-1 measures the change inmitochondria membrane potential by measuring red fluorescence withexcitation/emission at 560/595 nM, which is high for healthy cells andgreen fluorescence with excitation/emission at 485/535 nM), which is lowif cells are unhealthy.

Another advantage of the assay is that the assay can measure the effectof mitochondrial function of multiple compounds in either a 1 pointconcentration or a 9-point dose response curve in a 96-well basedformat.

g. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the presentinvention whether prepared by synthetic processes or by metabolicprocesses. Preparation of the compounds by metabolic processes includesthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

The compounds of the present invention may be prepared by a variety ofprocesses well known for the preparation of compounds of this class. Forexample, the compounds of the present invention wherein the groups a,R¹, R², R³, R⁴, R⁵, U, V, W, X, Y, and Z, have the meanings as set forthin the Summary of the Invention section unless otherwise noted, can besynthesized as shown in Schemes 1-18.

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: Ac for acetyl; aq for aqueous; atm foratmosphere; DABCO for diazabicyclo[2.2.2]octane; DMF forN,N-dimethylformamide; Et for ethyl; EtOH for ethanol; HPLC for highpressure liquid chromatography; LC/MS for liquid chromatography/massspectroscopy; Me for methyl; MeOH for methanol; OAc for acetate; Ph forphenyl; psi for pounds per square inch; TFA for trifluoroacetic acid;THF for tetrahydrofuran; TMS for trimethylsilyl; Ts forp-toluenesulfonyl; TsCl for p-toluenesulfonyl chloride; TsO forp-toluenesulfonate; TsOH for p-toluenesulfonic acid; Xantphos for9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.

Compounds of formula (1-3), wherein R¹, R², R³ and R⁴ are as defined informulas (I), (II), (III), (IV), (V), and (VI), can be prepared asdescribed in Scheme 1. Benzophenone hydrazone, (1-1), can be reactedwith an aryl halide of formula (1-2), wherein Hal is chlorine, bromine,or iodine, in the presence of a palladium/ligand system such aspalladium(II) acetate and Xantphos in the presence of a base such assodium t-butoxide or triethylamine heated in a solvent such as tolueneto provide compounds of formula (1-3) (Wagaw, S.; Yang, B. H.; Buchwald,S. L. J. Am. Chem. Soc. 1999, 121(44), 10251-10263). Alternatively, arylhydrazines of formula (1-4) can be reacted with benzophenone in thepresence of a catalyst such as ammonium chloride or sulfuric acid in aheated solvent such as water, methanol or ethanol to give compounds offormula (1-3).

Compounds of formula (2-5), wherein R¹, R², R³, R⁴, R⁵, R⁶, U, V, W, Y,and Z are as defined in formula (I), can be prepared as described inScheme 2. Compounds of formula (1-3) or (1-4), can be reacted withketones of formula (2-1) in the presence of an acid under Fischerreaction conditions to give indoles of formula (2-2) (Wagaw, S.; Yang,B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121(44), 10251-10263.Hughes, D. L. Progress in the Fischer Indole Reaction. A Review. Org.Prep. Proced. Int. 1993, 25, 607-632. Humphrey, G. R.; Kuethe, J. K.Practical Methodologies for the Synthesis of Indoles. Chem. Rev.2006,106, 2875-2911.). Compounds of formula (2-2) can be treated with abase such as sodium hydride, sodium amide, lithium diisopropylamide orcesium carbonate and a compound of formula (2-3), wherein LG¹ is asuitable leaving group such as chlorine, bromine, iodine,p-toluenesulfonate, or trifluoromethanesulfonate, in solvents such asN,N-dimethylformamide, tetrahydrofuran, toluene, or ether to furnishcompounds of formula (2-5) which are representative of compounds offormula (I). Alternatively, compounds of formula (2-2) can be treatedwith a compound of formula (2-4) in the presence of sodium andhydroquinone in a heated (80-140° C.) solvent such as dimethyl sulfoxidefor 24-96 hours to give compounds of formula (2-5) which arerepresentative of compounds of formula (I). Compounds of formula (2-4)can be obtained commercially or synthesized by coupling potassiumvinyltrifluoroborate with an aryl or heteroaryl halide in the presenceof a catalyst such as palladium(II) chloride, a ligand such astriphenylphosphine, and a base such as cesium carbonate in a solventsuch as a mixture of tetrahydrofuran and H₂O heated at 70-90° C.

Compounds of formula (2-5), wherein R¹, R², R³, R⁴, R⁵, R⁶, U, V, W, Y,and Z are as defined in formula (I), can be prepared as described inScheme 3. Hydrazones of formula (1-3) can be alkylated with compounds offormula (2-3) using conditions described in Scheme 2 to supply compoundsof formula (3-1) (e.g., Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am.Chem. Soc. 1999, 44, 10251-10263). Alternatively, compounds of formula(3-1) can be prepared from anilines of formula (3-2). Anilines offormula (3-2) can be transformed to hydrazines of formula (3-3) asdescribed in U.S. Pat. No. 3,409,628. Specifically, anilines of formula(3-2) can be reacted with a vinylheteroaryl or vinylaryl compound in thepresence of sodium. Treatment with sodium nitrite and reduction withzinc in acetic acid produces the disubstituted hydrazine (3-3).Subsequently, compounds of formula (3-3) can be transformed to compoundsof formula (3-1) using the conditions in Scheme 1 for the conversion ofcompounds of formula (1-4) to compounds of formula (1-3). Compounds offormula (3-1) can then be reacted with ketones of formula (2-1) underthe conditions described in Scheme 2 for the conversion of compounds offormula (1-3) to compounds of formula (2-2) to furnish compounds offormula (2-5) which are representative of compounds of formula (I).Compounds of formula (3-3) can also be directly converted to compoundsof formula (2-5) using the conditions previously described for theconversion of compounds of formula (3-1) to compounds of formula (2-5).

Compounds of formula (4-1), wherein R¹, R², R³, R⁴, R⁵, R⁶, U, V, W, Y,and Z are as defined in formula (I), can be prepared as described inScheme 4. Compounds of formula (2-5) can be treated with a solution ofsodium in liquid ammonia/tetrahydrofuran to supply compounds of formula(4-1). Compounds of formula (2-5) can also be transformed to compoundsof formula (4-1) by treatment with borane-tetrahydrofuran complex in atrifluoroacetic acid solution (Berger, J.; Tahbaz, P.; McPhail, A. T.;Onan, K. D. Tetrahedron Lett. 1983, 24(24), 2469-2472). Alternatively,compounds of formula (2-5) can be converted to compounds of formula(4-1) by treatment with sodium cyanoborohydride in a mixture oftrifluoroacetic acid and methanol. Compounds of formula (4-1) arerepresentative of compounds of formula (I).

Compounds of formula (5-2) and compounds of formula (5-3), wherein R¹,R², R³, R⁴, R⁶, V, Y, and Z are as defined in formula (IV), can beprepared as described in Scheme 5. Compounds of formula (5-1) can beconverted to compounds of formula (5-2) with the methodologies describedin Scheme 2 or Scheme 3. Subsequently, compounds of formula (5-2) can betransformed to compounds of formula (5-3) under the reduction conditionsdescribed in Scheme 4. Compounds of formula (5-2) and (5-3) arerepresentative of compounds of formula (IV).

Compounds of formula (6-3) and compounds of formula (6-4), wherein R¹,R², R³, R⁴, and R⁶ are as defined in formula (VI), can be prepared asdescribed in Scheme 6. Compounds of formula (6-1) (Becker, D. P.; Flynn,D. L. Synthesis 1992, (11), 1080-1082) can be converted to compounds offormula (6-2) by treatment with diazomethane or(trimethylsilyl)diazomethane in a solvent such as tetrahydrofuran orether (von E. Doering, W.; Virladeanu, L.; Andrews, D. W.; Pagnotta, M.J. Am. Chem. Soc. 1985, 107, 428-432). Compounds of formula (6-2) can beconverted to compounds of formula (6-3) with the methodologies describedin Scheme 2 or Scheme 3. Subsequently, compounds of formula (6-3) can betransformed to compounds of formula (6-4) under the reduction conditionsdescribed in Scheme 4. Compounds of formula (6-3) and (6-4) arerepresentative of compounds of formula (VI).

Compounds of formula (2-2) wherein, R¹, R², R³, R⁴, R⁵, U, V, W, and Yare as defined in formula (I), can be prepared as described in Scheme 7.Anilines of formula (7-1) can be treated with iodine monochloride in thepresence of calcium carbonate in methanol to supply compounds of formula(7-2). Alternatively, an aqueous solution of compounds of formula (7-1)and potassium carbonate or sodium bicarbonate can be treated with iodineto provide compounds of formula (7-2) (Xiao, W.-J.; Alper, H. J. Org.Chem. 1999, 64, 9646-9652). Compounds of formula (7-2) can be convertedto compounds of formula (2-2) by treatment with compounds of formula(2-1) in the presence of palladium(II) acetate anddiazabicyclo[2.2.2]octane (DABCO) in solvent such as methanol (Chen, C.;Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org.Chem. 1997, 62, 2676-2677). Compounds of formula (2-2) can then beemployed as described in Scheme 2.

Compounds of formula (8-1) wherein, R¹, R², R³, R⁴, V, Y, and Z are asdefined in formula (IV), can be prepared as described in Scheme 8.Anilines of formula (7-2) can be converted to compounds of formula (8-1)upon treatment with compounds of formula (5-1) under the conditionsdescribed in Scheme 7. Compounds of formula (8-1) can then be employedin Scheme 2 substituting for compounds of formula (2-2).

Compounds of formula (9-1) wherein, R¹, R², R³, and R⁴ are as defined informula (VI), can be prepared as described in Scheme 9. Anilines offormula (7-2) can be converted to compounds of formula (9-1) upontreatment with compounds of formula (6-2) under the conditions describedin Scheme 7. Compounds of formula (9-1) can then be employed in Scheme 2substituting for compounds of formula (2-2).

Compounds of formula (10-7), wherein R¹, R², R³ and R⁴ are as defined informulas (I), (II), (III), (IV), (V), and (VI), and G¹ is defined in theSummary of the Invention, can be prepared as described in Scheme 10.Phthalic anhydride, (10-1), can be reacted with arylhydrazines (1-4) inchloroform, ethanol, acetic acid, or in toluene in the presence of anacid to supply compounds of formula (10-2). Compounds of formula (10-2)can be converted to compounds of formula (10-6) in a variety of ways.For example, compounds of formula (10-2) can be reacted with vinylarylor vinylheteroaryl groups of formula (2-4) in the presence of sodiumoptionally in the presence of hydroquinone in solvents such asN,N-dimethylformamide or dimethyl sulfoxide to give compounds of formula(10-6). Compounds of formula (10-2) can also be reacted with compoundsof formula (10-3), wherein LG¹ is a suitable leaving group such aschlorine, bromine, iodine, p-toluenesulfonate, ortrifluoromethanesulfonate, in the presence of a base such as sodiumhydride, sodium amide, lithium diisopropylamide or cesium carbonate insolvents such as N,N-dimethylformamide, tetrahydrofuran, toluene, orether to furnish compounds of formula (10-6). Compounds of formula(10-6) can also be obtained by reacting compounds of formula (10-2) withaldehydes of formula (10-4) under reductive amination conditions such assodium triacetoxyborohydride in acetic acid or the hydrochloride salt ofcompounds of formula (10-2) with aldehydes (10-4) in the presence ofborane pyridine complex. Compounds of formula (10-2) can also beconverted to compounds of formula (10-6) by reacting with compounds offormula (10-5) first in the presence of a base such as sodium hydride orlithium diisopropylamide and subsequently with triethylsilane andtrifluoroacetic acid or hydrogen in the presence of palladium. Compoundsof formula (10-6) are transformed to compounds of formula (10-7) bytreatment with hydrazine hydrate in optionally heated ethanol (Nara, S.;Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Synth. Commun. 2003, 33,87098). Compounds of formula (10-7) can be used in Schemes 3, 5 or 6 toproduce compounds of formulas (I), (IV), or (VI).

Compounds of formula (10-6), wherein R¹, R², R³ and R⁴ are as defined informulas (I), (II), (III), (IV), (V), and (VI), and G¹ is defined in theSummary of the Invention, can be prepared as described in Scheme 11.N-Aminophthalimide (11-1) can be reacted under the various alkylatingconditions described in Scheme 10 for the conversion of compounds offormula (10-2) to compounds of formula (10-6) to supply compounds offormula (11-2). Compounds of formula (11-2) can be arylated withcompounds of formula (1-2) wherein Hal is a halogen limited to iodine orbromine, in the presence of palladium(II) acetate, tri-t-butyl phosphinein the presence of cesium carbonate in heated toluene (Kang, H.-M.;Shin, I.-J.; Kim, H.-Y.; Cho, C.-G. Org. Lett. 2006, 8, 2047-2050).Alternatively, compounds of formula (11-2) can be transformed tocompounds of formula (10-6) by treatment with compounds of formula(1-2), wherein Hal is limited to iodine, in the presence of copper(II)acetate, cesium carbonate, and 1,10-phenanthroline. Another alternativeinvolves the reaction of compounds of formula (11-2) with compounds offormula (11-3) in the presence of a base such as triethylamine and acatalyst such as copper(II) acetate in optionally heated dichloromethane(Nara, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Synth. Commun. 2003,33, 87098). Compounds of formula (10-6) can then be further used asdescribed in Scheme 10.

Compounds of formulas (2-4), (10-3), (10-4) and (10-5) that are used inSchemes 10 and 11 can be prepared by one skilled in the art. G¹ is asdescribed in the Summary of the Invention and for the methodologydescribed in Scheme 12 is preferentially aryl or heteroaryl. Forexample, esters of formula (12-1) can be converted to compounds offormula (2-4) in a three step process. To that end, esters of formula(12-1) can be first reduced with a reducing agent such as lithiumaluminum hydride and then subsequently oxidized with a reagent such asmanganese(II) oxide to supply the corresponding aldehyde. The aldehydecan then be reacted with methylene(triphenyl)phosphorane to furnishcompounds of formula (2-4), wherein R^(5a) is hydrogen. Alternatively,compounds of formula (2-4), wherein R^(5a) is hydrogen, can be preparedfrom aryl bromides or heteroaryl bromides of formula (12-2). Accordinglycompounds of formula (12-2) are reacted with either potassiumvinyltrifluoroborate or triethoxy(vinyl)silane in the presence of a basesuch as sodium hydroxide and a palladium catalyst such as palladiumacetate or phenone oxime-derived palladacycles either conventionallyheated or heated in a microwave (Alacid, E.; Najera, C. J. Org. Chem.2008, 73(6), 2315-2322. Gordillo, A.; de Jesus, E.; Lopez-Mardomingo, C.Chem. Comm. 2007, 39, 4056-4058.).

Compounds of formula (12-1) can also be converted to compounds offormula (10-4). Once again, esters of formula (12-1) can be firstreduced with a reducing agent such as lithium aluminum hydride and thenoxidized with a reagent such as manganese(II) oxide to supply thecorresponding aldehyde. Subsequent Wittig reaction with(methoxymethyl)triphenylphosphonium chloride and t-butoxide in mixtureof glyme and toluene (Kawai, A.; Hara, O.; Hamada, Y.; Shiori, T.Tetrahedron Lett. 1988, 29(48), 6331-6334) followed by hydrolysis inaqueous acid provides aldehydes of formula (10-4).

Compounds of formula (10-3) can be prepared from either compounds offormula (2-4) or compounds of formula (10-4). Aldehydes of formula(10-4) can be reacted with a reducing agent such as sodium borohydrideto supply the corresponding alcohol. The alcohol can be converted to aleaving group by reaction with a sulfonyl chloride such asp-toluenesulfonyl chloride or methanesulfonyl chloride in the presenceof a base such as triethylamine or diisopropylethylamine to furnishcompounds of formula (10-3) wherein the leaving group, LG¹, is asulfonate. Compounds of formula (2-4) can also be converted to compoundsof formula (10-3). In a one-step process, compounds of formula (2-4) canbe reacted with a dialkylborane such as disiamylborane or9-borabicyclo[3.3.1]nonane (9-BBN) in the presence of iodine to givecompounds of formula (10-3), wherein LG¹ is iodine. Alternatively,compounds of formula (2-4) can first be converted to the correspondingprimary alcohols by hydroboration with a dialkylborane followed bytreatment with sodium hydroperoxide. The intermediate alcohols can thenbe converted to sulfonates of formula (10-3) as previously describedgiving compounds of formula (10-3), wherein LG¹ is p-toluenesulfonate ormethanesulfonate.

Compounds of formula (10-5) also can be prepared in more than one way.One option is to convert compounds of formula (12-3) to compounds offormula (10-5) by treatment with trimethylsulfonium iodide in thepresence of a base such as tert-butoxide in a solvent such astert-butanol (Boa, A. N.; Canavan, S. P.; et al. Bioorg. Med. Chem.2005, 13, 1945-1967). As an alternative approach, compounds of formula(2-4) can be converted to the epoxides of formula (10-5) by treatmentwith m-chloroperoxybenzoic acid in the presence of a base such as sodiumbicarbonate in a mixture of water and dichloromethane (Kamabe, M.;Miyazaki, T.; Hashimoto, K.; Shirahama, H. Heterocycles 2002, 56(1-2),105-111).

Compounds of formula (13-3), wherein a, R¹, R², R³ and R⁴ are as definedin formulas (I), (II), (III), (IV), (V), and (VI), G¹ is defined in theSummary of the Invention, and b represents the optionally protectedbicyclic, tricyclic, or spirocyclic ring systems of compounds offormulas (I), (II), (III), (IV), (V), and (VI), can be prepared asdescribed in Scheme 13. Compounds of formula (13-1) can be treated withcompounds of formula (13-2), wherein G² is pyridazinyl, pyrimidinyl ortriazinyl and Hal is chlorine, bromine or iodine, in the presence of abase such as potassium tert-butoxide or sodium hydride in a heatedsolvent such as N,N-dimethylformamide to provide compounds of formula(13-3). Compounds of formula (13-1) can be reacted with compounds offormula (13-2), wherein Hal is bromine or iodine and G² is pyridinyl, inthe presence of a base such as sodium carbonate, potassium carbonate,potassium phosphate or cesium acetate in the presence of copper and/orcopper(I) iodide in a heated solvent such as toluene, dimethylsulfoxide, chlorobenzene, or nitrobenzene to provide compounds offormula (13-3). Alternatively, compounds of formula (13-1) can bereacted with compounds of formula (13-2) in a palladium-mediatedcross-coupling reaction. Accordingly, compounds of formulas (13-1) and(13-2) can be combined in the presence of a catalyst such asbis(tri-t-butylphosphine and a base such as sodium t-butoxide in aheated solvent such as dioxane. The heating may be either conventionalor achieved with microwave irradiation.

Compounds of formula (13-4), wherein a, R¹, R², R³ and R⁴ are as definedin formulas (I), (II), (III), (IV), (V), and (VI), and b represents theoptionally protected bicyclic, tricyclic, or spirocyclic ring systems ofcompounds of formulas (I), (II), (III), (IV), (V), and (VI), can beprepared as described in Scheme 13. Compounds of formula (13-1) can becoupled with compounds of formula G^(A)-Hal, wherein G^(A) is aryl orheteroaryl and Hal is bromine or iodine, to provide compounds of formula(13-4). The coupling can be accomplished in the presence of a catalystsuch as bis(tri-t-butylphosphine)palladium(0) and a base such as sodiumtert-butoxide in a solvent such as dioxane with heating to 140-170° C.either conventionally or in a microwave oven to provide compounds offormula (13-4). Alternatively, a nucleophilic aromatic substitutionreaction may be carried out on compounds of formula (13-1) when G^(A) isaryl substituted with one or more electron withdrawing groups such asnitro or cyano and Hal is limited to fluorine. Accordingly, compounds offormula (13-1) an be combined with the arylfluoride in the presence of abase such as sodium hydride in an optionally heated solvent such asN,N-dimethylformamide to give compounds of formula (13-4).

Compounds of formula (13-5), wherein a, R¹, R², R³ and R⁴ are as definedin formulas (I), (II), (III), (IV), (V), and (VI), and b represents theoptionally protected bicyclic, tricyclic, or spirocyclic ring systems ofcompounds of formulas (I), (II), (III), (IV), (V), and (VI), can beprepared as described in Scheme 13. Compounds of formula (13-1) can besulfonylated with compounds of formula G^(A)SO₂Cl, wherein G^(A) is arylor heteroaryl, in the presence of a base such as potassium tert-butoxidein a solvent such as tetrahydrofuran to provide compounds of formula(13-5).

Compounds of formula (13-6), wherein a, R¹, R², R³ and R⁴ are as definedin formulas (I), (II), (III), (IV), (V), and (VI), and b represents theoptionally protected bicyclic, tricyclic, or spirocyclic ring systems ofcompounds of formulas (I), (II), (III), (IV), (V), and (VI), can beprepared as described in Scheme 13. Compounds of formula (13-1) can bereacted with Br—CH═CHG^(A) in the presence ofbis(tri-t-butylphosphine)palladium(0) and a base such as potassiumtert-butoxide in a solvent such as dioxane with heating to 90-120° C.either conventionally or in a microwave oven to provide compounds offormula (13-6). Alternatively, reaction conditions includen-butyllithium, a catalyst such as bis(dibenzylidene-acetone)palladium,a ligand such as tri-tert-butylphosphine, in a solvent mixture such as1,2-dimethoxyethane and toluene heated for 12 to 24 hours at 60-80° C.to furnish compounds of formula (13-6). Compounds of formula (13-6) canalso be prepared by reacting compounds of formula (13-1) with ≡-G^(A) inthe presence of sodium and hydroquinone in a solvent such as dimethylsulfoxide heated to 80-120° C. for 12 to 24 hours. Compounds of formula(13-6) can then by reduced in the presence of hydrogen and a catalystsuch as PtO₂ in an optionally heated solvent such as isopropanol toprovide compounds of formula (13-7).

Compounds of formula (13-8), (13-9), and (13-10), wherein a, R¹, R², R³and R⁴ are as defined in formulas (I), (II), (III), (IV), (V), and (VI),and b represents the optionally protected bicyclic, tricyclic, orspirocyclic ring systems of compounds of formulas (I), (II), (III),(IV), (V), and (VI), can be prepared as described in Scheme 13.Accordingly, compounds of formula (13-1) can be reacted with ethylbromoacetate in the presence of a base such as potassium tert-butoxidein a solvent such as tetrahydrofuran at or near ambient temperature over8 to 24 hours to supply compounds of formula (13-8). Compounds offormula (13-8) can be hydrolyzed to compounds of formula (13-9) in thepresence of aqueous sodium hydroxide heated in a solvent such asethanol. Compounds of formula (13-9) can be coupled with an amine offormula G^(A)NH₂ using amide bond forming conditions well known to oneskilled in the art to provide compounds of formula (13-10). One set ofamide bond forming conditions include1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,hydroxybenzotriazole, 4-(dimethylamino)pyridine stirred indichloromethane for 2 to 24 hours.

In all instances above, when b represents a protected bicyclic,tricyclic, or spirocyclic ring systems of compounds of formulas (I),(II), (III), (IV), (V), and (VI), one skilled in the art will know theappropriate deprotection conditions to reveal the compounds of formulas(I), (II), (III), (IV), (V), and (VI).

Compounds of formulas (14-2), (14-3), (14-4), (14-5), and (14-6) whereinR¹, R², R³, R⁴, R⁶, a, U, V, W, Y, an Z are as defined in formulas (I)can be prepared from compounds of formula (14-1). Compounds of formula(14-1) can be reacted with aldehydes of formula R^(A)CHO under reductiveamination conditions to provide compounds of formula (14-2). R^(A) canbe alkyl, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroaryl,heteroarylalkyl, or heterocycle. For example, compounds of formula(14-1) can be treated with aldehydes of formula R^(A)CHO in the presenceof sodium cyanoborohydride in the presence of an acid such as aceticacid in methanol to provide compounds of formula (14-2). Compounds offormula (14-1) can be reacted with sulfonates of R^(B)OSO₂R^(C), whereinR^(B) is alkyl or haloalkyl and R^(C) is trifluoromethyl or p-tolyl, inthe presence of a base such as triethylamine or diisopropylethylamine ina solvent such as N,N-dimethylformamide which can optionally be heatedto provide compounds of formula (14-3). Compounds of formula (14-1) canbe reacted with ClC(O)OR^(A) in a solvent such as tetrahydrofuran toprovide compounds of formula (14-4). Compounds of formula (14-1) canalso be reacted with acid chlorides of formula ClC(O)R^(A) or sulfonylchlorides of formula ClSO₂R^(A) in the presence of a base such astriethylamine or diisopropylamine in a solvent such as dichloromethaneat or near ambient temperature to provide compounds of formulas (14-5)and (14-6), respectively. Compounds of formulas (14-2), (14-3), (14-4),(14-5), and (14-6) are representative of compounds of formula (I).

Compounds of formula (15-2), wherein a, R¹, R², R³ and R⁴ are as definedin formulas (I), (II), (III), (IV), (V), and (VI); and b represents thebicyclic, tricyclic, or spirocyclic ring systems of compounds offormulas (I), (II), (III), (IV), (V), and (VI); can be prepared asdescribed in Scheme 15. Accordingly, compounds of formula (15-2) can beprepared by treating compounds of formula (15-1), wherein R^(D) is I,Br, Cl or trifluoromethanesulfonate, and wherein one of R² or R³ isR^(D), with compounds of formula G^(B)-B(OR^(E))₂, wherein G^(B) isaryl, heteroaryl or cyclopropyl and R^(E) is hydrogen, alkyl or joinedtogether with the atoms to which they are attached form a dioxoborolane.The reaction typically requires the use of a base and a catalyst.Examples of bases include but are not limited to potassium carbonate,potassium tert-butoxide, sodium carbonate, potassium phosphate, cesiumcarbonate, and cesium fluoride. Examples of catalysts include but arenot limited to tetrakis(triphenylphosphine)palladium(0),dichloro[1,1′-ferrocenylbis(diphenyl-phosphine)]palladium(II)dichloromethane, bis(dibenzylidene-acetone)palladium, palladium(II)acetate in the presence of a ligand such as tricyclohexylphosphine, andtrans-dichlorobis(triphenylphosphine)palladium(II). The reaction may beconducted in a solvent such as but not limited to water, dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,2-propanol, tetrahydrofuran and the like or mixtures thereof. Thereaction may be conducted at ambient or elevated temperatures.

Compounds of formula (16-3), wherein a, R¹, R², R³ and R⁴ are as definedin formulas (I), (II), (III), (IV), (V), and (VI); and b represents thebicyclic, tricyclic, or spirocyclic ring systems of compounds offormulas (I), (II), (III), (IV), (V), and (VI); can be prepared asdescribed in Scheme 16. Compounds of formula (1-3) can be treated withan acid chloride of formula R^(F)C(O)Cl, wherein R^(F) is aryl,heteroaryl, arylalkyl, or heteroarylalkyl, in the presence of a basesuch as triethylamine or diisopropylamine in a base such asN,N-dimethylformamide to provide compounds of formula (16-2). Compoundsof formula (16-2) can then be transformed to compounds of formula (16-3)according to the methodology described in Scheme 3, Scheme 5 or Scheme6.

Compounds of formula (17-4) wherein R¹, R², R³ and R⁴ are as defined informulas (I), (II), (III), (IV), (V), and (VI), and R^(F) is aryl,heteroaryl, arylalkyl, or heteroarylalkyl can be prepared as shown inScheme 17. Carboxylic acids of formula R^(F)CO₂H can be coupled withanilines of formula (3-2) using standard amide bond forming reactionconditions well known to one skilled in the art to give compounds offormula (17-1). One procedure usesO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate in the presence of diisopropylethylamine. Compoundsof formula (17-1) can be reduced to compounds of formula (17-2) withborane-tetrahydrofuran complex in refluxing tetrahydrofuran. Treatmentof compounds of formula (17-2) with sodium nitrite in an acid solutionprovides compounds of formula (17-3). Compounds of formula (17-3) can bereduced with zinc in the presence of ammonium carbonate to givecompounds of formula (17-4). An alternative for the production ofcompounds of (17-4) involves the alkylation of compounds of formula(1-4) with compounds of formula R^(F)CH₂-LG¹, wherein LG¹ is a suitableleaving group such as chlorine, bromine, iodine, p-toluenesulfonate, ortrifluoromethanesulfonate. Compounds of formula (1-4) can be reactedwith compounds of formula R^(F)CH₂-LG¹ in the presence of a base such astriethylamine or diisopropylethylamine in a heated solution of ethanolto give compounds of formula (17-4). Alternatively, compounds of formula(1-4) can be reacted with compounds of formula R^(F)CH₂-LG¹ in thepresence of a base such as sodium amide in a cooled solution oftetrahydrofuran to give compounds of formula (17-4). Compounds offormula (17-4) can be substituted for compounds of formula (3-3) inScheme 3.

Compounds of formula (18-4) wherein a, R¹, R², R³, R⁴ and R⁶ are asdefined in formula (IV) can be prepared as shown in Scheme 18. Compoundsof formula (18-1), which can be prepared with the methodologiesdescribed in Scheme 2 or Scheme 8, can be reacted withborane-tetrahydrofuran complex in a cooled solution of tetrahydrofuranto furnish the N-borane complex of compounds of formula (18-2).Compounds of formula (18-2) can be converted to compounds of formula(18-3) using the methodologies shown in Scheme 2 or Scheme 13. Compoundsof formula (18-3) are transformed to compounds of formula (18-4) withtreatment with hydrochloric acid in a solvent such as ethyl acetate.Compounds of formula (18-4) are representative of compounds of formula(IV).

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions may be worked up in the conventionalmanner, e.g., by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

h. EXAMPLES

The compounds and processes of the present invention will be betterunderstood by reference to the following Examples, which are intended asan illustration of and not a limitation upon the scope of theapplication.

Example 12,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 1A2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

In a 100 mL round-bottomed flask were combined p-tolylhydrazinehydrochloride (1.58 g, 10 mmol; Aldrich),8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.392 g, 10.00 mmol; Aldrich),and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reactionmixture was heated to 80° C. for 2.5 hours, then cooled to roomtemperature. The solvent was decanted, and the residue was dissolved inwater (20 mL) and basified with solid potassium carbonate to pH ˜12.This solution was extracted with dichloromethane (3×50 mL), and thecombined organic phases were dried over magnesium sulfate. Afterremoving the solvent under vacuum, the resulting solid wasrecrystallized from ether to afford the title compound: ¹H NMR (300 MHz,CDCl₃) δ ppm 2.43 (s, 3H), 2.55 (s, 3H), 2.82 (m, 4H), 3.64 (s, 2H),6.93 (d, J=7 Hz, 1H), 7.18-7.12 (m, 2H), 7.87 (br s, 1H); MS (DCI/NH₃)m/z 201 (M+H)⁺.

Example 1B2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction flask with a septum cap was charged with 30% sodium metaldispersion in paraffin wax (0.14 g, 1.86 mmol; Aldrich) and a solutionof 2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(0.30 g, 1.33 mmol; Example 1A) in dimethyl sulfoxide (2 mL). The vesselwas sealed, flushed with nitrogen, and stirred for 10 minutes. Asolution of 2-methyl-5-vinylpyridine (0.24 g, 1.99 mmol; prepared asdescribed in International Publication No. WO 2001017968) andhydroquinone (0.036 g, 0.33 mmol, Aldrich) in anhydrous dimethylsulfoxide (1.5 mL) was added and the reaction mixture was heated at 100°C. for 72 hours. After cooling the reaction mixture to room temperature,it was poured into water and extracted with ethyl acetate (4×25 mL). Thecombined organic extracts were washed with brine, concentrated, andpurified by preparative HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile inbuffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 15 minutes] to afford the title compound: MS(DCI/NH₃) m/z 346 (M+H)⁺.

Example 1C2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indolehydrochloride

A solution of the product from Example 1B (0.17 g, 0.49 mmol) in ethylacetate (4 mL) was treated with a solution of HCl in dioxane (4 M, 0.25mL, 0.98 mmol; Aldrich), added dropwise. After stirring for 20 minutes,the solid was collected by filtration, rinsed with ethyl acetate, anddried for 10 hours at 75° C. under high vacuum to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.72-2.09 (m, 1H),2.15-2.32 (m, 1H), 2.35-2.48 (m, 3H), 2.45-2.64 (m, 2H), 2.64-2.74 (m,3H), 2.88-3.08 (m, 3H), 3.22-3.31 (m, 3H), 3.65 (dd, J=17.1, 4.8 Hz,1H), 4.23-4.58 (m, 3H), 4.97-5.12 (m, 1H), 6.87-7.24 (m, 2H), 7.27-7.43(m, 1H), 7.75 (t, J=8.9 Hz, 1H), 8.05-8.24 (m, 1H), 8.26-8.42 (m, 1H);MS (DCI/NH₃) m/z 346 (M+H)⁺.

Example 29-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 2A 1-azabicyclo[3.2.2]nonan-4-one

An ice-cooled solution (5° C.) of (trimethylsilyl)diazomethane/hexane (2N, 30 mL, 60 mmol; Aldrich) under nitrogen was treated dropwise with asolution of quinuclidin-3-one (7500 mg, 60 mmol) in dry tetrahydrofuran(40 mL). Methanol (20 mL) was added, and the yellow solution was warmedto room temperature, stirred for 24 hours, and quenched to colorless byaddition of acetic acid. After a few minutes, saturated aqueous sodiumcarbonate (15 mL) was added. The organic layer was separated, and theaqueous solution was extracted with methylene chloride (3×50 mL). Thecombined organic layer and extracts were dried over magnesium sulfate,and concentrated in vacuo to give the titled compound. The material wasused directly for next step without further purification.

Example 2B 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

In a 100 mL round-bottomed flask were combined p-tolylhydrazinehydrochloride (1.58 g, 10 mmol; Aldrich), 1-azabicyclo[3.2.2]nonan-4-one(1.392 g, 10.00 mmol; Example 2A), and concentrated sulfuric acid (5 mL)in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5hours, then cooled to room temperature. The solvent was decanted, andthe residue was dissolved in water (20 mL) and basified with solidpotassium carbonate to pH ˜12. This solution was extracted withdichloromethane (3×50 mL), and the combined organic phases were driedover magnesium sulfate. After removing the solvent under vacuum, theresulting solid was further purified by silica gel column chromatographyeluting with 20% methanol-dichloromethane to supply the title compound:¹H NMR (300 MHz, CDCl₃) δ ppm 2.07-1.97 (m, 4H), 2.43 (s, 3H), 2.89 (m,1H), 3.1 (m, 2H), 3.3 (m, 2H), 4.25 (s, 2H), 6.9 (m, 1H), 7.17 (m, 2H),76 (br s, 1H); MS (DCI/NH₃) m/z 227 (M+H)⁺.

Example 2C9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A mixture of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg,1.0 mmol; Example 2B), sodium (46 mg, 2 mmol, 30-35% dispersion isparaffin wax; Aldrich), hydroquinone (0.083 mL, 1.0 mmol; Aldrich) and2-methyl-5-vinylpyridine (238 mg, 2.0 mmol) in dry dimethyl sulfoxide(10 mL) was purged with nitrogen, then heated to 100° C. with stirringfor 72 hours. The mixture was filtered and purified by preparative HPLC(Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute,5-95% gradient of acetonitrile in 0.1% trifluoroacetic acid, over 15minutes) to afford the title compound as the trifluoroacetic acid salt:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.07 (m, 2H), 2.24-2.37 (m,2H), 2.40 (s, 3H), 2.61 (s, 3H), 3.19 (t, J=6.5 Hz, 2H), 3.35-3.50 (m,3H), 3.56-3.69 (m, 2H), 4.49 (t, J=6.7 Hz, 2H), 4.70 (s, 2H), 6.98 (d,J=8.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.19 (s, 1H), 7.56 (d, J=8.3 Hz,1H), 7.90 (dd, J=7.9, 2.0 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H); MS (DCI/NH₃)m/z 346 (M+H)⁺.

Example 35-[6-(4-iodophenyl)pyridazin-3-yl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(113 mg, 0.499 mmol; Example 1A) and 3-chloro-6-(4-iodophenyl)pyridazine(190 mg, 0.599 mmol, US Patent No. 2005159597) was combined withpotassium tert-butoxide (67 mg, 0.599 mmol) in dry N,N-dimethylformamide(8 mL) under a nitrogen atmosphere, and the mixture was heated to 50° C.with stirring for 16 hours. After cooling to room temperature, themixture was filtered and purified by preparative HPLC (Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradientof acetonitrile in 0.1% trifluoroacetic acid, over 15 minutes) to affordthe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 2.02-2.19 (m, 1H), 2.29-2.75 (m, 3H), 2.48 (s, 3H),3.01 (s, 3H), 3.19 (d, J=18.2 Hz, 1H), 3.68-3.96 (m, 1H), 4.29-4.39 (m,1H), 5.10-5.24 (m, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.46 (s, 1H), 7.53 (d,J=8.3 Hz, 1H), 7.90-8.00 (m, 4H), 8.05-8.15 (m, 1H), 8.37 (d, J=9.1 Hz,1H); MS (DCI/NH₃) m/z 507 (M+H)⁺.

Example 42-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 4A2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

4-Tolylhydrazine hydrochloride (1.90 g, 12.0 mmol) and tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.70 g, 12.0 mmol; Fluka)were heated at 50° C. in anhydrous dioxane (80 mL) for one hour.Sulfuric acid (3.2 mL) was added dropwise, and the resulting mixture washeated at 80° C. overnight. After cooling the mixture to roomtemperature, the dioxane phase was decanted. The remaining residue wasdissolved in methanol (12 mL) and added slowly to a stirred solution ofconcentrated ammonium hydroxide (30 mL) kept at room temperature with awater bath. The resulting mixture was extracted with ethyl acetate (3×),and the combined organic phases were washed with brine, dried (sodiumsulfate), concentrated, and purified by chromatography (silica gel, 0-5%gradient of concentrated aqueous ammonium hydroxide in acetonitrile) toafford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.59-1.72(m, 1H), 1.93-2.25 (m, 3H), 2.54 (d, J=16 Hz, 1H), 3.25 (dd, J=16 Hz,4.7, 1H), 3.91-3.99 (m, 1H), 4.49 (d, J=4.8 Hz, 1H), 6.83 (d, J=8.2 Hz,1H), 7.12 (d, J=8.2 Hz, 1H), 7.19 (s, 1H); MS (ESI) m/z 213 (M+H)⁺.

Example 4B2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A suspension of2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (170 mg,0.80 mmol; Example 4A), hydroquinone (9 mg, 0.08 mmol), and ˜32% sodiumin paraffin (79 mg, 1.1 mmol; Aldrich) in anhydrous dimethyl sulfoxide(800 μL) was sealed in a septum-capped reaction tube. After thoroughlyevacuating and purging the vessel with nitrogen,2-methyl-5-vinylpyridine (143 mg, 1.2 mmol, International PublicationNo. WO2001/017968) was added, and the reaction was stirred at 100° C.for 48 hours. The thick mixture was cooled to room temperature, pouredinto water (5 mL), and extracted with ethyl acetate (3×). The combinedorganic phases were washed with water, filtered through diatomaceousearth, dried (Na₂SO₄), concentrated, and purified by chromatography onsilica (0-5% gradient of concentrated aqueous ammonium hydroxide inacetonitrile). The resulting material was purified further byreverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammoniumhydroxide)] to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.10-1.26 (m, 1H), 1.84-2.06 (m, 4H), 2.40 (s, 3H), 2.43 (s, 3H),2.86 (dd, J=16 Hz, 4.6, 1H), 2.97 (ddd, J=14 Hz, 5.4, 5.4, 1H), 3.09(ddd, J=14 Hz, 9.0, 6, 1H), 3.75-3.86 (m, 1H), 4.14 (ddd, J=15 Hz, 9.0,5.4, 1H), 4.30 (ddd, J=15 Hz, 6, 5.4, 1H), 4.44 (d, J=4.6 Hz, 1H), 6.90(d, J=8.3 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H),7.20-7.25 (m, 2H), 7.75 (d, J=2.1 Hz, 1H); MS (ESI) m/z 332 (M+H)⁺.

Example 5(7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers of the mixture of Example 4B were separatedby preparative chiral supercritical fluid chromatography (ChiralPak®OD-H 5 μm 21×250 mm column; flow rate 40 mL/minute; gradient of 10-50%CH₃OH/CO₂ containing 0.1% diethylamine) to afford the free base of thetitle compound as the second-eluting enantiomer. This material wasdissolved in ethyl acetate and treated with 4 M HCl in dioxane (2equivalents). The resulting precipitate was collected by filtration anddried to afford the title compound as the dihydrochloride salt: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.51-1.73 (m, 1H), 2.12-2.39 (m, 3H), 2.41(s, 3H), 2.49-2.68 (m, 4H), 3.01-3.26 (m, 3H), 4.19-4.35 (m, 1H),4.35-4.52 (m, 2H), 5.14 (s, 1H), 6.98 (d, J=9.8 Hz, 1H), 7.18 (d, J=8.1Hz, 1H), 7.32 (s, 1H), 7.39-7.52 (m, 1H), 7.66-7.78 (m, 1H), 8.00 (s,1H); MS (DCI/NH₃) m/z 332 (M+H)⁺. [α]_(D) −65 (c 0.5, CH₃OH).

Example 6(7R,10S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers of the mixture of Example 4B were separatedby preparative chiral supercritical fluid chromatography (ChiralPak®OD-H 5 μm 21×250 mm column; flow rate 40 mL/minute; gradient of 10-50%CH₃OH/CO₂ containing 0.1% diethylamine) to afford the free base of thetitle compound as the first-eluting enantiomer. This material wasdissolved in ethyl acetate and treated with 4 M HCl in dioxane (2equiv). The resulting precipitate was collected by filtration and driedto afford the title compound as the dihydrochloride salt: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.51-1.73 (m, 1H), 2.12-2.39 (m, 3H), 2.41 (s,3H), 2.49-2.68 (m, 4H), 3.01-3.26 (m, 3H), 4.19-4.35 (m, 1H), 4.35-4.52(m, 2H), 5.14 (s, 1H), 6.98 (d, J=9.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H),7.32 (s, 1H), 7.39-7.52 (m, 1H), 7.66-7.78 (m, 1H), 8.00 (s, 1H); MS(DCI/NH₃) m/z 332 (M+H)⁺.

Example 7(7R,10S)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers of the mixture of Example 1B were separatedby preparative chiral supercritical fluid chromatography (ChiralPak®OD-H 5 μm 21×250 mm column; flow rate 40 mL/minute; gradient of 10-50%CH₃OH/CO₂ containing 0.1% diethylamine, 20 minutes) to afford the freebase of the title compound as the first-eluting enantiomer (0.104 g,0.301 mmol). This material was dissolved in warm ethanol (2 mL) andtreated with a solution of D-tartaric acid (0.045 g, 0.301 mmol) in warmethanol (2 mL). Upon cooling, a solid formed, which was collected byfiltration to afford the title compound as the D-tartaric acid salt: ¹HNMR (300 MHz, methanol-d₄): δ ppm 1.45 (s, 1H), 2.12 (s, 1H), 2.31-2.53(m, 7H), 2.73-3.00 (m, 2H), 3.05-3.22 (m, 2H), 4.28-4.57 (m, 3H),4.82-5.02 (m, 9H), 7.06 (s, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.24-7.46 (m,3H), 7.71 (s, 1H); MS (DCI/NH₃) m/z 346 (M+H)⁺.

Example 8(7S,10R)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers of the mixture of Example 1B were separatedby preparative chiral supercritical fluid chromatography (ChiralPak®OD-H 5 μm 21×250 mm column; flow rate 40 mL/minute; gradient of 10-50%CH₃OH/CO₂ containing 0.1% diethylamine, 20 minute) to afford the freebase of the title compound as the second-eluting enantiomer (0.104 g,0.301 mmol). This material was dissolved in warm ethyl acetate (2 mL)and ethanol (0.5 mL) and treated with hydrogen chloride/dioxane (4 M;0.158 ml, 0.632 mmol), added dropwise. Upon cooling, a solid formedwhich was collected by filtration to afford the title compound as thedihydrochloride salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 1.48 (s, 1H),1.97 (s, 1H), 2.25-2.88 (m, 10H), 2.88-3.15 (m, 3H), 4.23 (s, 3H), 5.08(d, J=4.9 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 7.23 (s, 2H), 7.35 (s, 1H),7.46 (s, 1H), 7.60 (s, 1H), 8.15 (s, 1H), 8.74 (s, 1H); MS (DCI/NH₃) m/z346 (M+H)⁺.

Example 95-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(0.226 g, 0.999 mmol; Example 1A), sodium (30-35% dispersion inparaffin; 0.095 g, 1.364 mmol; Aldrich), 2-chloro-5-vinylpyridine (0.209g, 1.498 mmol; J. Chem. Soc. Chem. Commun. 1994, 15, 1775), hydroquinone(11 mg, 0.100 mmol; Aldrich), and dimethyl sulfoxide (3 mL), and thensealed. The reaction vessel was evacuated and flushed with nitrogen(10×), then heated to 100° C. for 24 hours. After cooling the mixture toroom temperature, it was poured into water, extracted with ethyl acetate(3×), and then purified twice by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient over15 minutes of acetonitrile in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.16-1.31 (m, 1H),1.72-1.86 (m, 2H), 2.10-2.30 (m, 5H), 2.46 (s, 3H), 2.69 (dd, J=16.3,4.4 Hz, 1H), 3.04 (ddd, J=25.2, 13.9, 6.5 Hz, 2H), 3.45 (t, J=5.4 Hz,1H), 4.12 (d, J=4.8 Hz, 1H), 4.19 (t, J=6.7 Hz, 2H), 6.94-7.03 (m, 2H),7.10 (d, J=7.4 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.28 (s, 1H), 8.04 (d,J=2.4 Hz, 1H); MS (DCI) m/z 366/368 (M+H)⁺.

Example 10(7R,10S)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the mixture of Example 9 (400 mg, 1.09mmol) were separated by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-30%gradient of CH₃OH—CO₂ containing 0.1% diethylamine) to obtain the titlecompound as the first eluting peak: ¹H NMR (300 MHz, CDCl₃) δ ppm1.16-1.31 (m, 1H), 1.72-1.86 (m, 2H), 2.10-2.30 (m, 5H), 2.46 (s, 3H),2.69 (dd, J=16.3, 4.4 Hz, 1H), 3.04 (ddd, J=25.2, 13.9, 6.5 Hz, 2H),3.45 (t, J=5.4 Hz, 1H), 4.12 (d, J=4.8 Hz, 1H), 4.19 (t, J=6.7 Hz, 2H),6.94-7.03 (m, 2H), 7.10 (d, J=7.4 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.28(s, 1H), 8.04 (d, J=2.4 Hz, 1H); MS (DCI) m/z 366/368 (M+H)⁺.

Example 11(7S,10R)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the mixture of Example 9 (400 mg, 1.09mmol) were separated by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-30%gradient of CH₃OH—CO₂ containing 0.1% diethylamine) to obtain the titlecompound as the second eluting peak: ¹H NMR (300 MHz, CDCl₃) δ ppm1.16-1.31 (m, 1H), 1.72-1.86 (m, 2H), 2.10-2.30 (m, 5H), 2.46 (s, 3H),2.69 (dd, J=16.3, 4.4 Hz, 1H), 3.04 (ddd, J=25.2, 13.9, 6.5 Hz, 2H),3.45 (t, J=5.4 Hz, 1H), 4.12 (d, J=4.8 Hz, 1H), 4.19 (t, J=6.7 Hz, 2H),6.94-7.03 (m, 2H), 7.10 (d, J=7.4 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.28(s, 1H), 8.04 (d, J=2.4 Hz, 1H); MS (DCI) m/z 366/368 (M+H)⁺.

Example 1211-ethyl-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(76 mg, 0.23 mmol; Example 4), acetic acid (34 μL, 0.59 mmol), andacetaldehyde (26 μL, 0.47 mmol) in methanol (1.5 mL) was treated withsodium cyanoborohydride (29 mg, 0.46 mmol), and stirred in a closed vialat room temperature for six days. Additional acetaldehyde (13 μL) andsodium cyanoborohydride (15 mg) were added and the mixture was stirredtwo more days, after which yet more acetaldehyde (12 μL) and sodiumcyanoborohydride (14 mg) were added. After another day, the mixture wasconcentrated, diluted with ethyl acetate, filtered, and purified byreverse-phase HPLC (C8 column, 10-95% gradient of acetonitrile inaqueous ammonium acetate) to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.28 (t, 3H), 1.38-1.53 (m, 1H), 2.11 (m, 1H), 2.29(m, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 2.86-3.00 (m, 2H), 3.00-3.19 (m, 3H), 4.06-4.18 (m, 1H), 4.18-4.32 (m, 1H), 4.39 (ddd, J=15 Hz, 6, 6, 1H),4.99 (d, J=5.0 Hz, 1H), 7.06 (dd, J=8.3 Hz, 1.5, 1H), 7.15 (d, J=8.0 Hz,1H), 7.29-7.36 (m, 3H), 7.72 (d, J=2.0 Hz, 1H); MS (ESI) m/z 360 (M+H)⁺.

Example 1311-(2-fluoroethyl)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(60 mg, 0.18 mmol; Example 4) and diisopropylethylamine (50 μL, 0.29mmol) in anhydrous N,N-dimethylformamide (500 μL) was treated dropwisewith 2-fluoroethyl tosylate (42 μL, 0.24 mmol). The reaction mixture wasstirred at room temperature for 1 hour and then heated at 50° C.overnight. After cooling the mixture to room temperature, it waspurified by reverse-phase HPLC (C8 column, 10-95% gradient ofacetonitrile in aqueous ammonium acetate) to afford the title compound:¹H NMR (500 MHz, methanol-d₄) δ ppm 1.21 (m, 1H), 1.76 (dd, J=9.4, 9.4,1H), 1.85 (d, J=16.5, 1H), 2.04-2.23 (m, 2H), 2.40 (s, 3H), 2.42 (s,3H), 2.55 (dd, J=9.6, 4.3, 1H), 2.60 (m, 1H), 2.64 (dd, J=16.5, 4.3,1H), 3.07 (m, 2H), 3.52 (m, 1H), 4.23-4.27 (m, 3H), 4.44 (m, 1H), 4.54(m, 1H), 6.94 (d, J=8.3, 1H), 7.09 (d, J=7.9, 1H), 7.19 (s, 1H), 7.21(dd, J=7.9, 2.2, 1H), 7.24 (d, J=8.3, 1H), 7.73 (d, J=2.1, 1H); MS (ESI)m/z 378 (M+H)⁺.

Example 142-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-11-(2,2,2-trifluoroethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(60 mg, 0.18 mmol; Example 4) and diisopropylethylamine (50 μL, 0.29mmol) in anhydrous N,N-dimethylformamide (500 μL) was cooled with awater-ice bath and then treated dropwise with 2,2,2-trifluoroethyltriflate (35 μL, 0.24 mmol). After 5 minutes the bath was removed andthe reaction mixture was stirred at room temperature for 6.5 hours, thendiluted with acetonitrile and purified by reverse phase HPLC (C8 column,10-95% gradient of acetonitrile in aqueous ammonium acetate) to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.12-1.25 (m,1H), 1.69-1.80 (m, 1H), 1.86 (d, J=17 Hz, 1H), 2.04-2.24 (m, 2H), 2.41(s, 3H), 2.41 (s, 3H), 2.55 (dd, J=17 Hz, 4.4, 1H), 2.78-2.92 (m, 2H),3.08 (t, J=6.2 Hz, 2H), 3.47-3.56 (m, 1H), 4.20-4.32 (m, 3H), 6.96 (d,J=8.3 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 7.14-7.21 (m, 2H), 7.27 (d, J=8.3Hz, 1H), 7.75 (d, J=2.1 Hz, 1H); MS (ESI) m/z 414 (M+H)⁺.

Example 15 ethyl(7R,10S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate

(7R,10S)-2-Methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(40.8 mg, 0.123 mmol; Example 6) in tetrahydrofuran (3.0 mL) was treatedwith ethyl carbonochloridate (0.014 ml, 0.148 mmol; Aldrich), addeddropwise. After 1 hour, water (5 mL) was added and the aqueous solutionwas extracted with CH₂Cl₂. The organic layer was dried over magnesiumsulfate, filtered, and concentrated. The resulting material was purifiedby reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 20 minutes] to provide the title compound: ¹H NMR (300 MHz, CDCl₃)δ ppm 1.10-1.38 (m, 5H), 1.81-2.03 (m, 2H), 2.06-2.25 (m, 2H), 2.46 (s,3H), 2.56 (s, 3H), 3.00 (m, 2H), 3.98-4.26 (m, 4H), 4.57 (dd, J=14.1,12.5 Hz, 1H), 5.10-5.36 (m, 1H), 6.90-7.08 (m, 2H), 7.16 (d, J=8.7 Hz,1H), 7.30-7.37 (m, 2H), 8.21 (s, 1H); MS (ESI) m/z 404 (M+H)⁺.

Example 16 ethyl(7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate

A solution of(7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(109 mg, 0.329 mmol; Example 5) in tetrahydrofuran (3.0 mL) was treatedwith ethyl carbonochloridate (0.31 ml, 0.323 mmol; Aldrich), addeddropwise. After 1 hour, water (5 mL) was added and the aqueous solutionwas extracted with CH₂Cl₂. The organic layer was dried over MgSO₄,filtered, and concentrated. The resulting material was purified bypreparative HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20minutes] to provide the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm1.10-1.38 (m, 5H), 1.81-2.03 (m, 2H), 2.06-2.25 (m, 2H), 2.46 (s, 3H),2.56 (s, 3H), 3.00 (m, J=7.1, 2H), 3.98-4.26 (m, 4H), 4.57 (dd, J=14.1,12.5 Hz, 1H), 5.10-5.36 (m, 1H), 6.90-7.08 (m, 2H), 7.16 (d, J=8.7 Hz,1H), 7.30-7.37 (m, 2H), 8.21 (s, 1H); MS (ESI) m/z 404 (M+H)⁺.

Example 1711-(4-chlorobenzoyl)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(36 mg, 0.11 mmol; Example 4), 4-chlorobenzoyl chloride (0.015 mL, 0.12mmol; Aldrich) and triethylamine (0.015 mL, 0.11 mmol; Aldrich) inmethylene chloride (5 mL) was stirred at 25° C. for one hour. Thereaction mixture was reduced to dryness and the residue was purified bypreparative HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flowrate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammoniumhydroxide)] to afford the title compound: ¹H NMR (400 MHz, methanol-d₄)δ ppm 1.25-1.47 (m, 1H), 1.87-1.99 (m, 1H), 2.09-2.28 (m, 3H), 2.37-2.46(two m, 6H, amide rotamers), 2.75-2.90 (two dd, J=16.5, 4.3 Hz, 1H,amide rotamers), 3.05-3.13 (m, 2H), 4.20-4.39 (m, 2H), 4.91-5.04 (two m,1H, amide rotamers), 6.93-7.02 (two s, 1H, amide rotamers), 7.06-7.20(m, 2H), 7.21-7.51 (m, 6H), 7.74-7.83 (two s, 1H, amide rotamers); MS(APCI) m/z 470 (M+H)⁺.

Example 182-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-11-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(36 mg, 0.11 mmol; Example 4), 4-trifluoromethylbenzenesulfonyl chloride(29 mg, 0.12 mmol) and triethylamine (0.015 mL, 0.11 mmol) in methylenechloride (5 mL) was stirred at 25° C. for one hour. The reaction mixturewas reduced to dryness and the residue was purified by reverse-phaseHPLC [Waters XBridge™ RP18 column, 5 m, 30×100 mm, flow rate 40mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] toafford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.12-1.23(m, 1H), 1.70 (dd, J=16.6, 1.0 Hz, 1H), 1.82-1.96 (m, 1H), 2.05-2.21 (m,2H), 2.41 (s, 3H), 2.46 (s, 3H), 2.60 (dd, J=16.6, 4.7 Hz, 1H),2.70-2.81 (m, 1H), 2.85-2.97 (m, 1H), 3.65 (ddd, J=14.7, 9.1, 5.8 Hz,1H), 3.93 (ddd, J=14.6, 6.1, 4.7 Hz, 1H), 4.38-4.48 (m, 1H), 5.17 (d,J=4.7 Hz, 1H), 6.97 (two d, J=1.4 Hz, 1H, rotamers), 7.04-7.13 (m, 3H),7.24-7.34 (m, 3H), 7.63-7.71 (m, 3H); MS (APCI) m/z 540 (M+H)⁺.

Example 19(7R,10S)-2,11-dimethyl-5-[2-(2-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 19A(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers of the mixture of Example 1A were separatedby preparative chiral HPLC (Chiralpak® AD 50×400 mm column; flow rate100 mL/minute; 60:20:20:0.2 hexane-ethanol-methanol-diethylamine, 25°C.) to afford the title compound as the second-eluting peak.

Example 19B(7R,10S)-2,11-dimethyl-5-[2-(2-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 122 mg, 1.599 mmol; Aldrich) and hydroquinone (10.0 mg, 0.088mmol; Aldrich) and dimethyl sulfoxide (1 mL), and the vessel wasevacuated and flushed with nitrogen (3×). 2-Methyl-3-vinylpyridine (211mg, 1.767 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was added via asyringe and the vessel was again evacuated and flushed with nitrogen,and then heated at 100° C. for 72 hours. After cooling the reactionmixture, water (5 mL) was added, and the aqueous solution was extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were dried overMgSO₄, filtered, and concentrated. The resulting material was purifiedby reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 20 minutes] to provide the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.11-1.36 (m, 1H), 1.69-1.87 (m, 2H), 2.09 (s, 3H),2.12-2.30 (m, 5H), 2.40 (s, 3H), 2.70 (dd, J=16.1, 3.9 Hz, 1H), 3.12 (t,J=5.3 Hz, 2H), 3.34-3.46 (m, 1H), 4.12 (d, J=5.1 Hz, 1H), 4.19-4.44 (m,2H), 6.91 (d, J=9.5 Hz, 1H), 7.04-7.12 (m, 1H), 7.13-7.22 (m, 2H), 7.27(d, J=7.5 Hz, 1H), 8.17-8.25 (m, 1H); MS (DCI/NH₃) m/z 346 (M+H)⁺.

Example 202,11-dimethyl-5-[(Z)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with 30% sodium metaldispersion in paraffin wax (0.30 g, 4.0 mmol; Aldrich) and a solution of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(0.112 g, 0.495 mmol; Example 1A) in dimethyl sulfoxide (2 mL). Thevessel was sealed, flushed with nitrogen, and stirred for 10 minutes. Asolution of 3-ethynylpyridine (0.206 g, 2.0 mmol; Aldrich) andhydroquinone (0.072 g, 0.66 mmol; Aldrich) in anhydrous dimethylsulfoxide (1.5 mL) was added and the reaction mixture was heated at 100°C. for 16 hours. After the reaction mixture was cooled to roomtemperature, it was purified by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient over15 minutes of acetonitrile in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound as the minor alkene isomer: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.31-1.45 (m, 1H), 1.91 (t, J=9 Hz, 1H), 2.12-2.34 (m, 3H), 2.30(s, 3H), 2.38 (s, 3H), 2.90 (dd, J=17, 4 Hz, 1H), 3.41-3.48 (m, 1H),4.20 (d, J=5 Hz, 1H), 6.63 (d, J=8 Hz, 1H), 6.83-6.95 (m, 2H), 7.00 (d,J=8 Hz, 1H), 7.16-7.28 (m, 3H), 8.04 (d, J=2 Hz, 1H), 8.27 (dd, J=5, 2Hz, 1H); MS (DCI/NH₃) m/z 330 (M+H)⁺.

Example 21(7R,10S)-2,11-dimethyl-5-[(E)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The racemate of the title compound was obtained by reverse-phase HPLC[Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute,5-95% gradient over 15 minutes of acetonitrile in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] as themajor component from the reaction mixture of Example 20. The individualenantiomers were separated by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine) to afford the titlecompound as the first-eluting peak: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.61-1.76 (m, 1H), 1.93 (t, J=9 Hz, 1H), 2.23-2.36 (m, 2H), 2.41 (s,3H), 2.43 (s, 3H), 2.70 (d, J=17 Hz, 1H), 3.40 (dd, J=17, 4 Hz, 1H),3.61-3.70 (m, 1H), 4.22 (d, J=5 Hz, 1H), 6.81 (d, J=15 Hz, 1H), 7.06(dd, J=8, 1 Hz, 1H), 7.28 (s, 1H), 7.41 (dd, J=8, 5 Hz, 1H), 7.63 (d,J=8 Hz, 1H), 7.74 (d, J=15 Hz, 1H), 8.04 (dt, J=8, 2 Hz, 1H), 8.35 (dd,J=5, 2 Hz, 1H), 8.65 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 330 (M+H)⁺.

Example 22(7S,10R)-2,11-dimethyl-5-[(E)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The racemate of the title compound was obtained from the mixture ofExample 20. The individual enantiomers were separated by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine) to afford the title compound as the second-eluting peak:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.57-1.75 (m, 1H), 1.93 (t, J=9 Hz,1H), 2.26-2.37 (m, 2H), 2.41 (s, 3H), 2.43 (s, 3H), 2.70 (d, J=17 Hz,1H), 3.40 (dd, J=17, 4 Hz, 1H), 3.61-3.69 (m, 1H), 4.22 (d, J=5 Hz, 1H),6.81 (d, J=15 Hz, 1H), 7.06 (dd, J=8, 1 Hz, 1H), 7.28 (s, 1H), 7.41 (dd,J=8, 5 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.74 (d, J=15 Hz, 1H), 8.04 (dt,J=8, 2 Hz, 1H), 8.35 (dd, J=5, 2 Hz, 1H), 8.65 (d, J=2 Hz, 1H); MS(DCI/NH₃) m/z 330 (M+H)⁺.

Example 23(7S,10R)-2,11-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 23A(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers of the mixture of Example 1A were separatedby preparative chiral HPLC (Chiralpak® AD 50×400 mm column; flow rate100 mL/minute; 60:20:20:0.2 hexane-ethanol-methanol-diethylamine, 25°C.) to afford the title compound as the first-eluting peak.

Example 23B(E)-2-methyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyridine

A dry 500-mL round-bottom flask was charged withcarbonylchlorohydrido-tris(triphenylphosphine) ruthenium(II) (0.571 g,0.600 mmol; Aldrich) and dry toluene (80 mL) under nitrogen. Afterpinacolborane (3.19 ml, 22.00 mmol, Aldrich) and5-ethynyl-2-methylpyridine (2.343 g, 20 mmol; International PublicationNo. WO2005090333) were added, the mixture was stirred at roomtemperature for 16 hours. The reaction mixture was extracted with ether,then the extract was washed with water, dried over MgSO₄ andconcentrated. The resulting material was purified by flashchromatography (silica gel, hexanes/ethyl acetate, 3:1) to afford thetitle compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.31 (s, 12H), 2.55 (s,3H), 6.19 (d, J=19 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.36 (d, J=18 Hz, 1H),7.71 (dd, J=8, 2 Hz, 1H), 8.56 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 246(M+H)⁺.

Example 23C 5-(2-bromovinyl)-2-methylpyridine

A solution of(E)-2-methyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-pyridine(1.0 g, 4.08 mmol; Example 23B) in acetonitrile (10 mL) was treated withN-bromosuccinimide (0.346 mL, 4.08 mmol; Aldrich) and triethylamine(0.625 mL, 4.49 mmol; Aldrich) and stirred at room temperature for 16hours. Water was added and the mixture was extracted several times withethyl acetate. The combined organic extracts were concentrated, and theresulting material was purified by flash chromatography (silica gel,hexane/ethyl acetate, 3:1) to afford the title compound as a 1.2:1 Z/Emixture: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.54 (s, 3H), 2.57 (s, 3.6H),6.52 (d, J=14 Hz, 1.2H), 6.75-6.85 (d, J=14 Hz, 1H), 7.01-7.22 (m,4.4H), 7.52 (dd, J=8, 2 Hz, 1H), 8.07 (dd, J=8, 2 Hz, 1.2H), 8.43 (d,J=2 Hz, 1H), 8.66 (d, J=2 Hz, 1.2H); MS (DCI/NH₃) m/z 198/200 (M+H)⁺.

Example 23D(7S,100)-2,11-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A 30-mL reaction tube was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(453 mg; 2.0 mmol, Example 23A), 5-(2-bromovinyl)-2-methylpyridine (396mg, 2.00 mmol; Example 23C), bis(tri-t-butylphosphine)palladium(0) (51mg, 0.10 mmol; Aldrich), sodium t-butoxide (481 mg, 5.00 mmol; Aldrich)and anhydrous dioxane (8 mL). The vessel was flushed with nitrogen,sealed, and heated to 100° C. with stirring for 30 minutes. Aftercooling the mixture, it was quenched with water and extracted with ethylacetate. The organic phase was concentrated and purified byreverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 40 mL/minute, 5-95% gradient of methanol in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] toafford the title compound as the major product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.59-1.75 (m, 1H), 1.92 (t, J=9 Hz, 1H), 2.23-2.36(m, 2H), 2.40 (s, 3H), 2.43 (s, 3H), 2.52 (s, 3H), 2.68 (d, J=17 Hz,1H), 3.39 (dd, J=17, 4 Hz, 1H), 3.64 (t, J=5 Hz, 1H), 4.22 (d, J=5 Hz,1H), 6.77 (d, J=15 Hz, 1H), 7.05 (d, J=9 Hz, 1H), 7.25-7.32 (m, 2H),7.61 (d, J=9 Hz, 1H), 7.68 (d, J=15 Hz, 1H), 7.94 (dd, J=8, 2 Hz, 1H),8.50 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 24(7S,10R)-2,11-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

Purification of the mixture from Example 23D by reverse-phase HPLC[Waters XBridge™ C18 5 μm column, 30×100 mm, flow rate 40 mL/minute,5-95% gradient over 15 minutes of acetonitrile in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]afforded the title compound as the minor product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.32-1.45 (m, 1H), 1.87-1.96 (m, 1H), 2.12-2.29 (m,3H), 2.30 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 2.90 (dd, J=17, 4 Hz,1H), 3.42-3.49 (m, 1H), 4.20 (d, J=5 Hz, 1H), 6.60 (d, J=8 Hz, 1H),6.84-6.98 (m, 3H), 7.03-7.16 (m, 2H), 7.25 (s, 1H), 7.92 (d, J=2 Hz,1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 25(7R,10S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (212 mg,1.00 mmol; Example 4A) and 5-ethynyl-2-methylpyridine (586 mg, 5.00mmol; International Publication No. WO2005090333) was performed asdescribed in Example 20 to afford the racemate of the title compound.The individual enantiomers were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to afford the title compound as the first-eluting peak: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.37-1.53 (m, 1H), 1.99-2.13 (m, 3H), 2.29-2.36 (m,1H), 2.38 (s, 3H), 2.41 (s, 3H), 3.01 (dd, J=16, 5 Hz, 1H), 3.90 (t, J=6Hz, 1H), 4.55 (d, J=4 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.80-6.88 (m, 2H),6.90 (d, J=9 Hz, 1H), 7.01-7.14 (m, 2H), 7.28 (s, 1H), 7.93 (d, J=2 Hz,1H); MS (DCI/NH₃) m/z 330 (M+H)⁺.

Example 26(7S,10R)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (212 mg,1.00 mmol; Example 4A) and 5-ethynyl-2-methylpyridine (586 mg, 5.00mmol; WO2005090333) was performed as described in Example 20 to affordthe racemate of the title compound. The individual enantiomers wereseparated by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine) to afford the title compound asthe second-eluting peak: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.37-1.52(m, 1H), 1.97-2.15 (m, 3H), 2.32 (d, J=17 Hz, 1H), 2.38 (s, 3H), 2.40(s, 3H), 3.00 (dd, J=16, 4 Hz, 1H), 3.86-3.91 (m, 1H), 4.53 (d, J=4 Hz,1H), 6.58 (d, J=9 Hz, 1H), 6.80-6.88 (m, 2H), 6.90 (d, J=8 Hz, 1H),7.02-7.13 (m, 2H), 7.27 (s, 1H), 7.93 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z330 (M+H)⁺.

Example 27(7S,10R)-2,11-dimethyl-5-(2-pyridin-2-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.33 mmol; Example 23A), sodium (30-35% dispersion in paraffin;203 mg, 2.65 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 2-vinylpyridine (181 mg, 1.723 mmol;Aldrich) in dimethyl sulfoxide (1.5 mL) was added via a syringe and thevessel was again evacuated and flushed with nitrogen, and then heated at100° C. for 72 hours. After the mixture was cooled to room temperature,brine (2 mL) was added and the mixture was stirred for few minutes.Ethyl acetate (4 mL) was added and mixture was stirred for severalminutes at 40° C. The organic phase was separated, concentrated, and theresulting material was purified by reverse-phase HPLC (Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95% gradient of acetonitrilein 0.1% aqueous trifluoroacetic acid, flow rate 50 mL/minute) to affordthe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.37 (m, 1H), 1.72 (m, 2H), 1.95 (m, 1H), 2.39 (s,3H), 2.45 (s, 3H), 2.53 (m, 1H), 2.63 (m, 1H), 2.78 (m, 1H), 3.36 (m,2H), 3.53 (m, 1H), 4.65 (m, 2H), 7.00 (d, J=2 Hz, 1H), 7.05 (dd, J=2, 8Hz, 1H), 7.12 (dd, J=2, 8 Hz, 1H), 7.28 (m, 1H), 7.35 (dd, J=2, 8 Hz,1H), 7.65 (m, 1H), 8.65 (m, 1H); MS (ESI) m/z 332 (M+H)⁺.

Example 28(7S,10R)-5-[2-(5-ethylpyridin-2-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(210 mg, 0.93 mmol; Example 23A), sodium (30-35% dispersion in paraffin;142 mg, 1.86 mmol; Aldrich), hydroquinone (10.2 mg, 0.090 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 5-ethyl-2-vinylpyridine (161 mg, 1.206mmol; 3B Scientific) in dimethyl sulfoxide (1.5 mL) was added via asyringe and the vessel was again evacuated and flushed with nitrogen,and then heated at 100° C. for 72 hours. After the mixture was cooled toroom temperature, brine (2 mL) was added and the mixture was stirred forfew minutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.24 (t, J=7.6 Hz, 3H), 1.29(m, 1H), 1.85 (m, 2H), 2.17 (m, 1H), 2.45 (s, 3H), 2.50 (s, 3H), 2.55(m, 5H), 3.36 (m, 2H), 3.53 (m, 1H), 4.65 (m, 2H), 6.99 (d, J=2 Hz, 1H),7.05 (dd, J=8, 8 Hz, 1H), 7.28 (m, 1H), 7.49 (d, J=8 Hz, 1H), 8.11 (dd,J=2, 8 Hz, 1H), 8.45 (d, J=2 Hz, 1H); MS (ESI) m/z 360 (M+H)⁺.

Example 29(7S,10R)-2,11-dimethyl-5-(2-pyridin-4-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.33 mmol; Example 23A), sodium (30-35% dispersion in paraffin;203 mg, 2.65 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 4-vinylpyridine (181 mg, 1.723 mmol;ASDI Products) in dimethyl sulfoxide (1.5 mL) was added via a syringeand the vessel was again evacuated and flushed with nitrogen, and thenheated at 100° C. for 72 hours. After the mixture was cooled to roomtemperature, brine (2 mL) was added and the mixture was stirred for fewminutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.44 (m, 1H), 1.70 (m, 2H), 1.95 (m,1H), 2.30 (s, 3H), 2.44 (s, 3H), 2.55 (m, 1H), 2.75 (m, 1H), 2.78 (m,1H), 3.06 (m, 2H), 3.53 (m, 1H), 4.65 (m, 2H), 7.00 (d, J=2 Hz, 1H),7.05 (dd, J=8 Hz, 1H), 7.18 (dd, J=2, 8 Hz, 1H), 7.49 (d, J=8 Hz, 2H),8.45 (d, J=8 Hz, 2H); MS (ESI) m/z 332 (M+H)⁺.

Example 302,11-dimethyl-5-(2-pyrimidin-5-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 30A 5-vinylpyridmidine

A solution of potassium vinyltrifluoroborate (843 mg, 6.29 mmol;Aldrich), palladium(II) chloride (22 mg, 0.124 mmol; Aldrich),triphenylphosphine (99 mg, 0.377 mmol; Aldrich), cesium carbonate (6.15g, 18.87 mmol; Aldrich), and 5-bromopyrimidine (843 mg, 6.29 mmol;Aldrich) in tetrahydrofuran/H₂O (9:1; 10 mL) was heated at 85° C. undera nitrogen atmosphere for 24 hours. The reaction mixture was cooled toroom temperature, diluted with water (15 mL), and extracted withdichloromethane (2×25 mL). The combined organic extracts were dried overMgSO₄, filtered, concentrated, and the crude material was purified byflash chromatography (silica gel, 5-60% ethyl acetate in hexanes) toafford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 5.52 (d, J=11.1Hz, 1H), 5.93 (d, J=17.9 Hz, 1H), 6.66 (dd, J=17.5, 11.1 Hz, 1H), 8.76(s, 2H), 9.10 (s, 1H).

Example 30B2,11-dimethyl-5-(2-pyrimidin-5-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(150 mg, 0.663 mmol; Example 1A), sodium (30-35% dispersion in paraffin;91 mg, 1.193 mmol; Aldrich) and hydroquinone (7.30 mg, 0.066 mmol;Aldrich) and then sealed with a septum cap. Dimethyl sulfoxide (1 mL)and 5-vinylpyrimidine (71 mg, 0.663 mmol; Example 30A) were introducedthrough the septum and the vessel was evacuated and backfilled withnitrogen (˜10×). The mixture was heated at 100° C. for 3 days. Aftercooling, the reaction mixture was filtered and purified by reverse-phaseHPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40mL/minute, 5-95% gradient of acetonitrile in 0.1% trifluoroacetic acidover 15 minutes) to afford the title compound as the trifluoroaceticacid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.03 (d, J=2.7 Hz, 1H),2.21-2.33 (m, 1H), 2.43 (s, 5H), 2.53-2.65 (m, 2H), 2.89-3.09 (m, 6H),3.49-3.58 (m, 2H), 4.18-4.31 (m, 1H), 6.98 (s, 2H), 7.13-7.40 (m, 4H);MS (DCI/NH₃) m/z 333 (M+H)⁺.

Example 31(7R,10S)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 31A 2-methyl-5-vinylpyrimidine

A solution of potassium vinyltrifluoroborate (666 mg, 4.97 mmol;Aldrich), palladium(II) chloride (18 mg, 0.099 mmol; Aldrich),triphenylphosphine (78 mg, 0.298 mmol; Aldrich), cesium carbonate (4.86g, 14.91 mmol; Aldrich), and 2-methyl-5-bromopyrimidine (867 mg, 4.97mmol; AniChem) in tetrahydrofuran/H₂O (9:1; 10 mL) was heated at 85° C.under a nitrogen atmosphere for 24 hours. The reaction mixture wascooled to room temperature, diluted with water (15 mL), and extractedwith dichloromethane (2×25 mL). The combined organic extracts were driedover MgSO₄, filtered, concentrated, and the crude material was purifiedby flash chromatography (silica gel, 5-60% ethyl acetate in hexanes) toafford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.73 (s, 3H),5.44 (d, J=11.10 Hz, 1H), 5.86 (d, J=17.85 Hz, 1H), 6.63 (dd, J=17.85,11.10 Hz, 1H), 8.66 (s, 2H); MS (DCI/NH₃) m/z 121 (M+H)⁺, 138 (M+NH₄)⁺.

Example 31B(7R,10S)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.326 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 183 mg, 2.386 mmol; Aldrich) and hydroquinone (14.6 mg, 0.133mmol; Aldrich) and then sealed with a septum cap. Dimethyl sulfoxide (1mL) and 2-methyl-5-vinylpyrimidine (319 mg, 2.65 mmol; Example 31A) wereintroduced through the septum and the vessel was evacuated andbackfilled with nitrogen (˜10×). The mixture was heated at 100° C. for72 hours. After cooling, the reaction mixture was diluted with water (5mL), extracted with dichloromethane (3×10 mL) and concentrated. Thecrude residue was purified by reverse-phase HPLC [Waters XBridge™ C18 5μm 30×100 mm column, flow rate 40 mL/minute, 40-99% gradient of methanolin buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 20 minutes], and then purified further byreverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flowrate 40 mL/minute, 5-95% gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid) to afford the title compound as thetrifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.11-1.35(m, 1H), 1.73-1.89 (m, 1H), 2.08-2.34 (m, 5H), 2.39 (s, 3H), 2.48-2.69(m, 4H), 2.86 (dd, J=16.5, 4.6 Hz, 1H), 2.99-3.18 (m, 2H), 3.46 (s, 1H),4.15 (d, J=4.8 Hz, 1H), 4.18-4.44 (m, 2H), 6.92 (d, J=8.7 Hz, 1H),7.05-7.29 (m, 2H), 8.05 (s, 2H); MS (ESI) m/z 347 (M+H)⁺.

Example 32(7S,10R)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(400 mg, 1.78 mmol; Example 23A), sodium (30-35% dispersion in paraffin;271 mg, 3.53 mmol; Aldrich), hydroquinone (20.0 mg, 0.133 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 2-methyl-5-vinylpyrimidine (319 mg,2.65 mmol; Example 31A) in dimethyl sulfoxide (2 mL) was added via asyringe and the vessel was again evacuated and flushed with nitrogen,and then heated at 100° C. for 72 hours. After the mixture was cooled toroom temperature, brine (2 mL) was added and the mixture was stirred forfew minutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.28 (m, 1H), 1.70 (m, 2H),1.95 (m, 1H), 2.21 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.48 (m, 1H),2.75 (m, 1H), 2.78 (m, 1H), 3.06 (m, 2H), 3.53 (m, 1H), 4.65 (m, 2H),6.95 (dd, J=2, 8 Hz, 1H), 7.15 (dd, J=8, 1H), 7.2 (m, 1H), 8.05 (s, 2H);MS (ESI) m/z 347 (M+H)⁺.

Example 33(7R,10S)-2,11-dimethyl-5-[2-(6-methylpyridazin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(350 mg, 1.55 mmol, Example 19A) and 3-methyl-6-vinylpyridazine (260 mg,1.93 mmol; J. Med. Chem. 2005, 48, 1367-1383) was performed as describedin Example 1B to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δppm 1.17-1.27 (m, 1H), 1.70-1.84 (m, 1H), 1.95 (d, J=16.3 Hz, 1H),2.14-2.25 (m, 5H), 2.45 (s, 3H), 2.65 (s, 3H), 2.80 (dd, J=16.6, 4.1 Hz,1H), 3.35 (t, J=6.8 Hz, 2H), 3.43-3.51 (m, 1H), 4.12 (d, J=5.1 Hz, 1H),4.46 (t, J=6.4 Hz, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.94-7.04 (m, J=8.5 Hz,2H), 7.20 (d, J=8.1 Hz, 1H), 7.25 (s, 1H); MS (DCI/NH₃) m/z 347 (M+H)⁺.

Example 34(7R,10S)-2,11-dimethyl-5-[2-(5-methylpyrazin-2-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(235 mg, 1.04 mmol; Example 19A) and 2-methyl-5-vinylpyrazine (100 mg,0.83 mmol; prepared using methodology described in Molander, G. A.; etal. J. Org. Chem., 2006, 71, 9681-9686) was performed as described inExample 1B to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm1.23-1.37 (m, 1H), 1.83 (t, J=9.3 Hz, 1H), 1.98 (d, J=15.9 Hz, 1H),2.15-2.30 (m, 5H), 2.45 (s, 3H), 2.51 (s, 3H), 2.83 (dd, J=16.3, 4.1 Hz,1H), 3.16 (t, J=6.8 Hz, 2H), 3.49 (d, J=4.7 Hz, 1H), 4.13 (d, J=4.7 Hz,1H), 4.30-4.41 (m, 2H), 6.92-7.00 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.26(s, 1H), 7.92 (d, J=1.4 Hz, 1H), 8.41 (s, 1H); MS (DCI/NH₃) m/z 347(M+H)⁺.

Example 352,11-dimethyl-5-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(150 mg, 0.663 mmol; Example 1A), sodium (30-35% dispersion in paraffin;91 mg, 1.193 mmol; Aldrich) and hydroquinone (7.30 mg, 0.066 mmol;Aldrich) and then sealed with a septum cap. Dimethyl sulfoxide (1 mL)and 4-methyl-5-vinylthiazole (83 mg, 0.663 mmol; Aldrich) wereintroduced through the septum and the vessel was evacuated andbackfilled with nitrogen (˜10×). The mixture was heated at 100° C. for 3days. After cooling, the reaction mixture was filtered and purified byreverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flowrate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1%trifluoroacetic acid over 15 minutes) to afford the title compound asthe trifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.70(s, 2H), 1.77 (s, 3H), 2.10-2.31 (m, 2H), 2.43 (s, 5H), 2.65 (s, 2H),2.90 (s, 3H), 4.04-4.21 (m, 2H), 4.28-4.40 (m, 1H), 4.39-4.53 (m, 1H),6.92-7.17 (m, 1H), 7.19-7.39 (m, 2H), 8.76 (d, J=4.7 Hz, 1H); MS(DCI/NH₃) m/z 352 (M+H)⁺.

General Procedure A N-Arylation of Benzophenone Hydrazone

A flame-dried round bottom flask was evacuated, backfilled withnitrogen, and charged with palladium(II) acetate (0.01 equivalents;Aldrich), Xantphos (0.011 equivalents; Aldrich), and toluene (1 mL). Theflask was then capped with a septum, and the mixture was stirred at roomtemperature under nitrogen for approximately 5 minutes. The septum wasremoved, and benzophenone hydrazone (10.0 equivalents; Aldrich), arylhalide (10.0 equivalents), and sodium tert-butoxide (14.0 equivalents,Aldrich) were added, followed by additional toluene (9 mL). The flaskwas re-capped, flushed with nitrogen, and the evacuation-backfill cyclewas repeated two more times. The reaction mixture was heated at 80° C.overnight, then cooled to room temperature and diluted with ether (15mL). The resulting heterogeneous mixture was filtered through a pad ofsilica gel with rinsing with additional ether. The filtrate wasconcentrated in vacuo to afford the crude product which was carried onto the next step without further purification.

General Procedure B N-Alkylation of N-Aryl Benzophenone Hydrazone

A solution of an N-aryl benzophenone hydrazone (1.0 equivalent), alkylhalide (1.0-10.0 equivalents), and tetrabutylammonium iodide (0.001equivalents, Aldrich) in 1:1 dichloromethane/50% aqueous NaOH (0.3 M inhydrazone) was stirred vigorously at 40° C. overnight. After cooling,the reaction mixture was diluted with 15 mL water and extracted withdichloromethane (25 mL). The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford the crude productwhich was carried on to the next step without purification.

General Procedure C Procedure for Fischer Indolization of N-aryl-N-alkylBenzophenone Hydrazones

A solution of the crude N-aryl-N-alkyl benzophenone hydrazone in ethanol(5 mL/mmol) was treated with the ketone (1.5 equivalents) andp-toluenesulfonic acid monohydrate (2.0 equivalents), and the solutionwas heated to reflux until the hydrazone was consumed, as ascertained byLC/MS. The reaction mixture was cooled to room temperature, neutralizedwith saturated sodium bicarbonate solution, and extracted with ether(2×10 mL). The combined ether extracts were dried over magnesium sulfateand concentrated in vacuo. The resulting material was purified byreverse-phase HPLC (Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1%trifluoroacetic acid over 15 minutes) to afford the title compound asthe trifluoroacetate salt.

Example 362,11-dimethyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 36A 1-(diphenylmethylene)-2-p-tolylhydrazine

General procedure A was used to convert benzophenone hydrazone (6.31 g,32.3 mmol; Aldrich) and 1-bromo-4-methylbenzene 5.0 g, 29.2 mmol;Aldrich) into the title compound: MS (DCI/NH₃) m/z 287 (M+H)⁺.

Example 36B 2-(diphenylmethylene)-1-phenethyl-1-p-tolylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example36A) and 2-bromoethylbenzene (210 mg, 0.69 mmol; Aldrich) to the titlecompound: MS (DCI/NH₃) m/z 391 (M+H)⁺.

Example 36C2,11-dimethyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-phenethyl-1-p-tolylhydrazine (273 mg, 0.698mmol; Example 36B) and tropinone (131 mg, 1.05 mmol; Aldrich) to thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃)δ ppm 1.12-1.39 (m, 1H), 1.71-1.98 (m, 2H), 2.05-2.33 (m, 5H), 2.47 (s,3H), 2.65 (dd, J=16.5, 4.2 Hz, 1H), 2.88-3.20 (m, 2H), 3.32-3.54 (m,1H), 3.98-4.30 (m, 3H), 6.80-6.91 (m, 2H), 7.04-7.13 (m, 1H), 7.13-7.23(m, 3H), 7.26-7.33 (m, 1H), 7.39 (dd, J=19.3, 8.5 Hz, 1H); MS (DCI/NH₃)m/z 331 (M+H)⁺.

Example 372,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 37A2-(diphenylmethylene)-1-(2-methylphenethyl)-1-p-tolylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example36A) and 2-methylphenethylbromide (278 mg, 1.4 mmol; Aldrich) to thetitle compound: MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 37B2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-(2-methylphenethyl)-1-p-tolylhydrazine (300 mg,0.74 mmol; Example 37A) and tropinone (155 mg, 1.1 mmol; Aldrich) to thetitle compound as the trifluoroacetate salt: ¹H NMR (300 MHz, CDCl₃) δppm 1.12-1.39 (m, 1H), 1.71-1.98 (m, 2H), 2.05-2.33 (m, 5H), 2.35 (s,3H), 2.47 (s, 3H), 2.65 (dd, J=16.5, 4.2 Hz, 1H), 2.88-3.20 (m, 2H),3.32-3.54 (m, 1H), 3.98-4.30 (m, 3H), 7.04-7.20 (m, 4H), 7.24-7.42 (m,3H); MS (DCI/NH₃) m/z 345 (M+H)⁺.

Example 38(7R,10S)-2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088mmol; Aldrich) and then sealed with a septum cap. Dimethyl sulfoxide (1mL) and 1-methyl-2-vinylbenzene (209 mg, 1.77 mmol; Aldrich) wereintroduced through the septum and the vessel was evacuated andbackfilled with nitrogen (˜10×). The mixture was heated at 100° C. for72 hours. After cooling, the reaction mixture was filtered and purifiedby reverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column,30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm1.12-1.39 (m, 1H), 1.71-1.98 (m, 2H), 2.05-2.33 (m, 5H), 2.35 (s, 3H),2.47 (s, 3H), 2.65 (dd, J=16.5, 4.2 Hz, 1H), 2.88-3.20 (m, 2H),3.32-3.54 (m, 1H), 3.98-4.30 (m, 3H), 7.04-7.20 (m, 4H), 7.24-7.42 (m,3H); MS (DCI/NH₃) m/z 345 (M+H)⁺.

Example 39(7S,10R)-2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.33 mmol; Example 23A), sodium (30-35% dispersion in paraffin;203 mg, 2.65 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-methyl-2-vinylbenzene (204 mg, 1.723mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was added via a syringeand the vessel was again evacuated and flushed with nitrogen, and thenheated at 100° C. for 72 hours. After the mixture was cooled to roomtemperature, brine (2 mL) was added and the mixture was stirred for fewminutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.25 (m, 1H), 1.73 (m, 2H), 1.91 (m,1H), 2.25 (s, 3H), 2.35 (s, 3H), 2.42 (s, 3H), 2.48 (m, 1H), 2.75 (m,1H), 3.15 (m, 2H), 4.06 (m, 1H), 4.26 (m, 2H), 4.80 (m, 1H), 6.65 (d,J=8 Hz, 1H), 6.98 (m, 1H), 7.15 (m, 2H), 7.28 (m, 2H), 7.33 (d, J=8 Hz,1H); MS (ESI) m/z 345 (M+H)⁺.

Example 402,11-dimethyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 40A2-(diphenylmethylene)-1-(4-methylphenethyl)-1-p-tolylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example36A) and 4-methylphenethylbromide (278 mg, 1.4 mmol; Aldrich) to thetitle compound: MS (DCI/NH₃) m/z 404 (M+H)⁺.

Example 40B2,11-dimethyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-(4-methylphenethyl)-1-p-tolylhydrazine (300 mg,0.74 mmol; Example 40A) and tropinone (155 mg, 1.1 mmol; Aldrich) to thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃)δ ppm 1.12-1.39 (m, 1H), 1.71-1.98 (m, 2H), 2.05-2.33 (m, 5H), 2.35 (s,3H), 2.47 (s, 3H), 2.65 (dd, J=16.5, 4.2 Hz, 1H), 2.88-3.20 (m, 2H),3.32-3.54 (m, 1H), 3.98-4.30 (m, 3H), 6.70 (t, J=7.7 Hz, 1H), 6.99 (t,J=7.9 Hz, 1H), 7.06-7.17 (m, 3H), 7.26-7.45 (m, 2H); MS (DCI/NH₃) m/z345 (M+H)⁺.

Example 415-[2-(4-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 41A2-(diphenylmethylene)-1-(4-fluorophenethyl)-1-p-tolylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example36A) and 4-fluorophenethylbromide (1.38 g, 6.8 mmol; Aldrich) to thetitle compound: MS (DCI/NH₃) m/z 409 (M+H)⁺.

Example 41B5-[2-(4-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-(4-fluorophenethyl)-1-p-tolylhydrazine (300 mg,0.734 mmol; Example 41A) and tropinone (153 mg, 1.1 mmol; Aldrich) tothe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.14-1.35 (m, 1H), 1.68-1.88 (m, 2H), 2.10-2.29 (m, 5H),2.46 (s, 3H), 2.66 (dd, J=16.3, 4.4 Hz, 1H), 2.89-3.11 (m, 2H),3.36-3.54 (m, 1H), 4.07-4.24 (m, 3H), 6.84-6.88 (m, 2H), 6.90 (s, 2H),6.98 (dd, J=8.1, 1.4 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.27 (s, 1H); MS(DCI/NH₃) m/z 349 (M+H)⁺.

Example 425-[2-(3-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 42A2-(diphenylmethylene)-1-(3-fluorophenethyl)-1-p-tolylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example36A) and 3-fluorophenethylbromide (1.38 g, 6.7 mmol; Aldrich) to thetitle compound: MS (DCI/NH₃) m/z 409 (M+H)⁺.

Example 42B5-[2-(3-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-(3-fluorophenethyl)-1-p-tolylhydrazine (300 mg,0.734 mmol; Example 42A) and tropinone (153 mg, 1.1 mmol; Aldrich) tothe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.17-1.39 (m, 1H), 1.71-1.93 (m, 2H), 2.11-2.31 (m, 5H),2.41-2.55 (m, 3H), 2.58-2.75 (m, 1H), 2.89-3.15 (m, 2H), 3.35-3.52 (m,1H), 4.08-4.30 (m, 3H), 6.58-6.67 (m, 1H), 6.69-6.77 (m, 1H), 6.84-6.95(m, 1H), 6.95-7.04 (m, 1H), 7.12-7.24 (m, 2H), 7.25-7.31 (m, 1H); MS(DCI/NH₃) m/z 349 (M+H)⁺.

Example 435-[2-(2-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 1A), sodium (30-35% dispersion in paraffin;122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088 mmol;Aldrich) and then sealed with a septum cap. A solution of1-fluoro-2-vinylbenzene (162 mg, 1.326 mmol; Aldrich) in dimethylsulfoxide (1 mL) was introduced through the septum and the vessel wasevacuated and backfilled with nitrogen (˜10×). The mixture was heated at100° C. for 72 hours. After cooling, the reaction mixture was dilutedwith water (5 mL), extracted with dichloromethane, and purified byreverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column,30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm1.39-1.56 (m, 1H), 1.92-2.15 (m, 4H), 2.29 (d, J=16.3 Hz, 2H), 2.39-2.93(m, 5H), 3.13 (t, J=6.3 Hz, 2H), 4.09 (s, 1H), 4.15-4.39 (m, 2H), 4.82(s, 1H), 6.61-6.70 (m, 1H), 6.84-6.95 (m, 1H), 6.98-7.08 (m, 1H),7.09-7.23 (m, 3H), 7.31 (d, J=8.5 Hz, 1H); MS (ESI) m/z 349 (M+H)⁺.

Example 44(7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088mmol; Aldrich) and then sealed with a septum cap. A solution of1-chloro-4-vinylbenzene (245 mg, 1.767 mmol; Aldrich) in dimethylsulfoxide (1 mL) was introduced through the septum and the vessel wasevacuated and backfilled with nitrogen (˜10×). The mixture was heated at100° C. for 72 hours. After cooling, the reaction mixture the reactionmixture was diluted with water (5 mL), extracted with dichloromethane,and purified by reverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA column, 30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.30-1.54 (m, 1H), 2.03-2.21 (m, 2H), 2.47-2.48 (m, 3H), 2.52-2.62(m, 3H), 2.83-2.91 (m, 2H), 3.04-3.19 (m, 2H), 3.96-4.22 (m, 2H),4.26-4.39 (m, 1H), 4.38-4.52 (m, 1H), 4.89-5.01 (m, 1H), 6.84 (t, J=8.7Hz, 2H), 7.00-7.13 (m, 2H), 7.13-7.23 (m, 2H), 7.30 (s, 1H); MS (ESI)m/z 365 (M+H)⁺.

Example 45(7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.33 mmol; Example 23A), sodium (30-35% dispersion in paraffin;203 mg, 2.65 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-chloro-4-vinylbenzene (239 mg, 1.723mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was added via a syringeand the vessel was again evacuated and flushed with nitrogen, and thenheated at 100° C. for 72 hours. After the mixture was cooled to roomtemperature, brine (2 mL) was added and the mixture was stirred for fewminutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ 1.40 (m, 1H), 2.10 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.48 (m, 1H), 2.75 (m, 1H), 3.15 (m, 2H), 4.14 (m,1H), 4.23 (m, 2H), 4.85 (m, 1H), 6.25 (d, J=2 Hz, 1H), 6.99 (d, J=8 Hz,1H), 7.05 (m, 3H), 7.33 (d, J=8 Hz, 2H); MS (ESI) m/z 365 (M+H)⁺.

Example 46(7S,10R)-5-[2-(2-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.33 mmol; Example 23A), sodium (30-35% dispersion in paraffin;203 mg, 2.65 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-chloro-2-vinylbenzene (239 mg, 1.723mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was added via a syringeand the vessel was again evacuated and flushed with nitrogen, and thenheated at 100° C. for 72 hours. After the mixture was cooled to roomtemperature, brine (2 mL) was added and the mixture was stirred for fewminutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ 1.42 (m, 1H), 2.10 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.48 (m, 1H), 2.75 (m, 1H), 3.15 (m, 2H), 4.15 (m,1H), 4.34 (m, 2H), 4.89 (m, 1H), 6.60 (dd, J=2, 8 Hz, 1H), 6.99 (m, 1H),7.15 (m, 3H), 7.33 (m, 2H); MS (ESI) m/z 365 (M+H)⁺.

Example 475-[2-(4-bromophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.105 mmol; Example 1A), sodium (30-35% dispersion in paraffin;170 mg, 2.21 mmol; Aldrich), hydroquinone (12.0 mg, 0.11 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-bromo-4-vinylbenzene (303 mg, 1.657mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was added via a syringeand the vessel was again evacuated and flushed with nitrogen, and thenheated at 100° C. for 72 hours. After the mixture was cooled to roomtemperature, brine (2 mL) was added and the mixture was stirred for fewminutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.40 (m, 1H), 2.10 (m, 3H), 2.27 (s,3H), 2.42 (s, 3H), 2.48 (m, 1H), 2.75 (m, 1H), 3.15 (m, 2H), 4.15 (m,1H), 4.23 (m, 2H), 4.90 (m, 1H), 6.65 (d, J=8 Hz, 1H), 7.15 (m, 1H),7.35 (m, 5H); MS (ESI) m/z 410 (M+H)⁺.

Example 485-[2-(3-bromophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.33 mmol; Example 1A), sodium (30-35% dispersion in paraffin;203 mg, 2.65 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-bromo-3-vinylbenzene (303 mg, 1.66mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was added via a syringeand the vessel was again evacuated and flushed with nitrogen, and thenheated at 100° C. for 72 hours. After the mixture was cooled to roomtemperature, brine (2 mL) was added and the mixture was stirred for fewminutes. Ethyl acetate (4 mL) was added and mixture was stirred forseveral minutes at 40° C. The organic phase was separated, concentrated,and the resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.46 (m, 1H), 2.10 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.48 (m, 1H), 2.75 (m, 1H), 3.15 (m, 2H), 4.13 (m,1H), 4.23 (m, 2H), 4.89 (m, 1H), 6.55 (d, J=2 Hz, 1H), 7.15 (m, 3H),7.35 (m, 3H); MS (ESI) m/z 410 (M+H)⁺.

Example 492,11-dimethyl-5-{2-[4-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.1 mmol; Example 1A), sodium (30-35% dispersion in paraffin;169 mg, 2.21 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-(trifluoromethyl)-4-vinylbenzene(285 mg, 1.66 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was addedvia a syringe and the vessel was again evacuated and flushed withnitrogen, and then heated at 100° C. for 72 hours. After the mixture wascooled to room temperature, brine (2 mL) was added and the mixture wasstirred for few minutes. Ethyl acetate (4 mL) was added and mixture wasstirred for several minutes at 40° C. The organic phase was separated,concentrated, and the resulting material was purified by reverse-phaseHPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.37 (m, 1H), 2.05 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.55 (m, 1H), 2.88 (m, 1H), 3.19 (m, 2H), 4.11 (m,1H), 4.29 (m, 2H), 4.86 (m 1H), 6.95 (d, J=8 Hz, 2H), 7.15 (m, 1H), 7.35(m, 2H), 7.45 (d, J=8 Hz, 2H); MS (ESI) m/z 399 (M+H)⁺.

Example 502,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.1 mmol; Example 1A), sodium (30-35% dispersion in paraffin;169 mg, 2.21 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-(trifluoromethyl)-3-vinylbenzene(285 mg, 1.66 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was addedvia a syringe and the vessel was again evacuated and flushed withnitrogen, and then heated at 100° C. for 72 hours. After the mixture wascooled to room temperature, brine (2 mL) was added and the mixture wasstirred for few minutes. Ethyl acetate (4 mL) was added and mixture wasstirred for several minutes at 40° C. The organic phase was separated,concentrated, and the resulting material was purified by reverse-phaseHPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (m, 1H), 2.05 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.55 (m, 1H), 2.88 (m, 1H), 3.18 (m, 2H), 4.11 (m,1H), 4.29 (m, 2H), 4.85 (m, 1H), 7.02 (d, J=8 Hz, 1H), 7.15 (m, 2H),7.30 (m, 3H), 7.47 (d, J=8 Hz, 1H); MS (ESI) m/z 399 (M+H)⁺.

Example 51(7R,10S)-2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088mmol; Aldrich) and then sealed with a septum cap. A solution of1-trifluoromethyl-3-vinylbenzene (304 mg, 1.767 mmol; Aldrich) indimethyl sulfoxide (1 mL) was introduced through the septum and thevessel was evacuated and backfilled with nitrogen (˜10×). The mixturewas heated at 100° C. for 72 hours. After cooling, the reaction mixturethe reaction mixture was diluted with water (5 mL), extracted withdichloromethane, and purified by reverse-phase HPLC (Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95% gradient of acetonitrilein 0.1% aqueous trifluoroacetic acid, flow rate 50 mL/minute) to affordthe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.30-1.54 (m, 1H), 2.03-2.21 (m, 2H), 2.47-2.48 (m,3H), 2.52-2.62 (m, 3H), 2.83-2.91 (m, 2H), 3.04-3.19 (m, 2H), 3.96-4.22(m, 2H), 4.26-4.39 (m, 1H), 4.38-4.52 (m, 1H), 4.89-5.01 (m, 1H),7.02-7.11 (m, 1H), 7.18 (dd, J=18.5, 8.0 Hz, 2H), 7.27-7.33 (m, 1H),7.34-7.44 (m, 1H), 7.45-7.58 (m, 2H); MS (ESI) m/z 399 (M+H)⁺.

Example 52(7S,10R)-2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.1 mmol; Example 23A), sodium (30-35% dispersion in paraffin;169 mg, 2.21 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-(trifluoromethyl)-3-vinylbenzene(285 mg, 1.66 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was addedvia a syringe and the vessel was again evacuated and flushed withnitrogen, and then heated at 100° C. for 72 hours. After the mixture wascooled to room temperature, brine (2 mL) was added and the mixture wasstirred for few minutes. Ethyl acetate (4 mL) was added and mixture wasstirred for several minutes at 40° C. The organic phase was separated,concentrated, and the resulting material was purified by reverse-phaseHPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (m, 1H), 2.05 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.55 (m, 1H), 2.88 (m, 1H), 3.18 (m, 2H), 4.11 (m,1H), 4.29 (m, 2H), 4.85 (m, 1H), 7.02 (d, J=8 Hz, 1H), 7.15 (m, 2H),7.30 (m, 3H), 7.47 (d, J=8 Hz, 1H); MS (ESI) m/z 399 (M+H)⁺.

Example 532,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.1 mmol; Example 1A), sodium (30-35% dispersion in paraffin;169 mg, 2.21 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-(trifluoromethyl)-2-vinylbenzene(285 mg, 1.66 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was addedvia a syringe and the vessel was again evacuated and flushed withnitrogen, and then heated at 100° C. for 72 hours. After the mixture wascooled to room temperature, brine (2 mL) was added and the mixture wasstirred for few minutes. Ethyl acetate (4 mL) was added and mixture wasstirred for several minutes at 40° C. The organic phase was separated,concentrated, and the resulting material was purified by reverse-phaseHPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (m, 1H), 2.05 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.55 (m, 1H), 2.69 (m, 1H), 3.28 (m, 2H), 4.14 (m,1H), 4.29 (m, 2H), 4.90 (m, 1H), 6.66 (d, J=8 Hz, 1H), 7.15 (dd, J=2, 8Hz, 1H), 7.30 (m, 4H), 7.70 (d, J=8 Hz, 1H); MS (ESI) m/z 399 (M+H)⁺.

Example 54(7R,10S)-2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088mmol; Aldrich) and then sealed with a septum cap. A solution of1-trifluoromethyl-2-vinylbenzene (304 mg, 1.767 mmol; Aldrich) indimethyl sulfoxide (1 mL) was introduced through the septum and thevessel was evacuated and backfilled with nitrogen (˜10×). The mixturewas heated at 100° C. for 72 hours. After cooling, the reaction mixturethe reaction mixture was diluted with water (5 mL), extracted withdichloromethane, and purified by reverse-phase HPLC (Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95% gradient of acetonitrilein 0.1% aqueous trifluoroacetic acid, flow rate 50 mL/minute) to affordthe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.38 (m, 1H), 2.05 (m, 3H), 2.25 (s, 3H), 2.42 (s, 3H),2.55 (m, 1H), 2.69 (m, 1H), 3.29 (m, 2H), 4.16 (m, 1H), 4.29 (m, 2H),4.92 (m, 1H), 6.66 (d, J=8 Hz, 1H), 7.15 (dd, J=2, 8 Hz, 1H), 7.30 (m,4H), 7.70 (d, J=8 Hz, 1H); MS (ESI) m/z 399 (M+H)⁺.

Example 55(7S,10R)-2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.1 mmol; Example 23A), sodium (30-35% dispersion in paraffin;169 mg, 2.21 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-(trifluoromethyl)-2-vinylbenzene(285 mg, 1.66 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was addedvia a syringe and the vessel was again evacuated and flushed withnitrogen, and then heated at 100° C. for 72 hours. After the mixture wascooled to room temperature, brine (2 mL) was added and the mixture wasstirred for few minutes. Ethyl acetate (4 mL) was added and mixture wasstirred for several minutes at 40° C. The organic phase was separated,concentrated, and the resulting material was purified by reverse-phaseHPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (m, 1H), 2.05 (m, 3H), 2.25 (s,3H), 2.42 (s, 3H), 2.55 (m, 1H), 2.69 (m, 1H), 3.29 (m, 2H), 4.16 (m,1H), 4.29 (m, 2H), 4.92 (m, 1H), 6.66 (d, J=8 Hz, 1H), 7.15 (dd, J=2, 8Hz, 1H), 7.30 (m, 4H), 7.70 (d, J=8 Hz, 1H); MS (ESI) m/z 399 (M+H)⁺.

Example 565-[2-(4-methoxyphenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 1A), sodium (30-35% dispersion in paraffin;122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088 mmol;Aldrich) and then sealed with a septum cap. A solution of1-methoxy-4-vinylbenzene (178 mg, 1.326 mmol; Aldrich) in dimethylsulfoxide (1 mL) was introduced through the septum and the vessel wasevacuated and backfilled with nitrogen (˜10×). The mixture was heated at100° C. for 72 hours. After cooling, the reaction mixture was dilutedwith water (5 mL), extracted with dichloromethane, and purified byreverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column,30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm1.38 (m, 1H), 2.05 (m, 3H), 2.25 (s, 3H), 2.42 (s, 3H), 2.55 (m, 1H),2.69 (m, 1H), 3.29 (m, 2H), 4.16 (m, 1H), 4.29 (m, 2H), 4.92 (m, 1H),6.73-6.82 (m, 1H), 7.13 (d, J=8.7 Hz, 1H), 7.17-7.27 (m, 4H), 7.33 (d,J=7.9 Hz, 1H); MS (ESI) m/z 361 (M+H)⁺.

Example 57(7R,10S)-2,11-dimethyl-5-[(E)-2-phenylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(314 mg, 1.387 mmol; Example 19A) in toluene/1,2-dimethoxyethane (6 mL,5/1) under nitrogen atmosphere was treated with n-butyllithium (2 M incyclohexane; 694 μL, 1.387 mmol; Aldrich) at room temperature. Afterstirring the mixture for 30 minutes, bis(dibenzylidene-acetone)palladium(63.8 mg, 0.111 mmol; Aldrich), tri-tert-butylphosphine (1 M in toluene;222 μL, 0.222 mmol; Aldrich) and (E)-(2-bromovinyl)benzene (179 μL,1.389 mmol; ARVI Products) were added. The flask was purged withnitrogen again and heated at 70° C. for 18 hours. After cooling, thereaction mixture was filtered through a pad of diatomaceous earth andthe volatiles were evaporated. The residue was purified by flashchromatography (24 g silica gel, CH₃OH-10% concentrated NH₄OH) to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.33 (d, J=10.2Hz, 1H), 1.68 (m, 1H), 1.93 (t, J=9.3 Hz, 1H), 2.29 (m, 1H), 2.41 (s,3H), 2.42 (s, 3H), 2.67 (d, J=16 Hz, 1H), 3.34 (m, 1H), 3.65 (bs, 1H),4.23 (d, J=4 Hz, 1H), 6.79 (d, J=14.7 Hz, 1H), 7.04 (dd, J=1.4, 8 Hz,1H), 7.21 (m, 1H), 7.26 (s, 1H), 7.34 (m, 2H), 7.50 (m, 2H), 7.57 (m,2H); MS (ESI) m/z 329 (M+H)⁺.

Example 582,11-dimethyl-5-[(E)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(112 mg, 0.495 mmol, Example 1A) and 1-ethynyl-4-methylbenzene (232 mg,2.0 mmol; Aldrich) was performed as described in Example 20 to affordthe title compound as the minor isomer: ¹H NMR (300 MHz, methanol-d₄) δppm 1.60-1.71 (m, 1H), 1.87-1.96 (m, 1H), 2.21-2.32 (m, 2H), 2.33 (s,3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.65 (d, J=16 Hz, 1H), 3.34-3.43 (m,1H), 3.60-3.67 (m, 1H), 4.22 (d, J=4 Hz, 1H), 6.75 (d, J=15 Hz, 1H),7.03 (dd, J=8, 1 Hz, 1H), 7.16 (d, J=8 Hz, 2H), 7.26 (s, 1H), 7.38 (d,J=8 Hz, 2H), 7.49-7.56 (m, 2H); MS (DCI/NH₃) m/z 343=(M+H)⁺.

Example 59(7R,10S)-2,11-dimethyl-5-[(E)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), cesium fluoride (175 mg, 1.149 mmol;Aldrich), hydroquinone (9.7 mg, 0.088 mmol; Aldrich) and1-ethynyl-4-methylbenzene (123 mg, 1.060 mmol; Aldrich) and the vesselwas evacuated and flushed with nitrogen. Dimethyl sulfoxide (2 mL) wasadded and the vessel was again evacuated and flushed with nitrogen, andthen heated at 135° C. for 72 hours. After the mixture was cooled toroom temperature, it was filtered, concentrated, and the resultingmaterial was purified by reverse-phase HPLC (Phenomenex® Luna® C8(2) 5μm 100 Å AXIA column, 30×75 mm, 10-95% gradient of acetonitrile in 0.1%aqueous trifluoroacetic acid, flow rate 50 mL/minute) to afford thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.60 (m, 1H), 1.87 (m, 1H), 2.21 (m, 2H), 2.30 (s,3H), 2.42 (s, 3H), 2.42 (s, 3H), 2.65 (d, J=15.5 Hz, 1H), 3.39 (m, 1H),3.63 (m, 1H), 4.20 (d, J=3.5 Hz, 1H), 6.75 (d, J=15.5 Hz, 1H), 7.03 (dd,J=1, 8 Hz, 1H), 7.15 (d, J=8 Hz, 2H), 7.28 (s, 1H), 7.40 (d, J=8 Hz,2H), 7.52 (m, 2H); MS (ESI) m/z 343 (M+H)⁺.

Example 602,11-dimethyl-5-[(Z)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(112 mg, 0.495 mmol, Example 1A) and 1-ethynyl-4-methylbenzene (232 mg,2.0 mmol; Aldrich) was performed as described in Example 20. Additionalpurification by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100mm column, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in0.1% trifluoroacetic acid over 15 minutes) afforded the title compoundas the trifluoroacetic acid salt as the major isomer: ¹H NMR (300 MHz,pyridine-d₅) δ ppm 1.45-1.56 (m, 1H), 2.02-2.14 (m, 4H), 2.34-2.48 (m,5H), 2.66 (ddd, J=18, 12, 6 Hz, 1H), 2.74 (s, 3H), 2.98 (br. s, 1H),4.14 (dd, J=7, 5 Hz, 1H), 5.11 (d, J=5 Hz, 1H), 6.65 (d, J=9 Hz, 1H),6.73 (d, J=9 Hz, 1H), 6.87 (d, J=8 Hz, 2H), 6.93 (d, J=8 Hz, 2H), 7.10(d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.36 (s, 1H); MS (DCI/NH₃) m/z343 (M+H)⁺.

Example 61(7R,10S)-2,11-dimethyl-5-[(Z)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A portion of the racemic mixture from Example 60 (60 mg, 0.175 mmol) waspurified further by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine, over 20 minutes) toafford the title compound as the first-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.27-1.40 (m, 1H), 1.83-1.93 (m, 1H), 2.04-2.35(m, 3H), 2.23 (s, 3H), 2.28 (s, 3H), 2.41 (s, 3H), 2.80 (dd, J=17, 5 Hz,1H), 3.35-3.41 (m, 1H), 4.19 (d, J=5 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 6.74(d, J=8 Hz, 3H), 6.89 (dd, J=8, 1 Hz, 1H), 6.94 (d, J=8 Hz, 2H), 7.06(d, J=8 Hz, 1H), 7.24 (s, 1H); MS (DCI/NH₃) m/z 343 (M+H)⁺.

Example 62(7R,10S)-5-[(E)-2-(2,4-dimethylphenyl)vinyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 19A), sodium (30-35% dispersion inparaffin; 122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088mmol; Aldrich) and then sealed with a septum cap. A solution of1-ethynyl-2,4-dimethylbenzene (230 mg, 1.767 mmol; Aldrich) in dimethylsulfoxide (1 mL) was introduced through the septum and the vessel wasevacuated and backfilled with nitrogen (˜10×). The mixture was heated at100° C. for 72 hours. After cooling, the reaction mixture the reactionmixture was diluted with water (5 mL), extracted with dichloromethane,and purified by reverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA column, 30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.60 (m, 1H), 1.87 (m, 1H), 2.21 (m, 2H), 2.30 (s, 3H), 2.42 (s,3H), 2.42-2.48 (m, 8H), 2.65 (d, J=15.5 Hz, 1H), 3.39 (m, 1H), 3.63 (m,1H), 4.20 (d, J=3.5 Hz, 1H), 7.06-7.17 (m, 2H), 7.31-7.42 (m, 2H),7.45-7.53 (m, 1H), 7.54-7.64 (m, 1H); MS (ESI) m/z 356 (M+H)⁺.

Example 635-[(4-chlorophenyl)acetyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 63A2-(4-chlorophenyl)-N′-(diphenylmethylene)-N-p-tolylacetohydrazide

To an ice-chilled solution of 1-(diphenylmethylene)-2-p-tolylhydrazine(270 mg, 0.94 mmol; Example 36A) and N,N-diisopropyl-N-ethylamine (120mg, 0.94 mmol; Aldrich) in N,N-dimethylformamide (2.0 mL) was added2-(4-chlorophenyl)acetyl chloride (178 mg, 0.94 mmol; Alfa Aesar). After10 minutes the ice bath was removed and the reaction mixture was stirredat room temperature overnight (18 hours). The reaction mixture wasdiluted with water (10 mL) and extracted with dichloromethane (2×20 mL).The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated in vacuo to afford the crude product, whichwas carried on to the next step without further purification: LC/MS m/z439 (M+H)⁺.

Example 63 B5-[(4-chlorophenyl)acetyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(4-chlorophenyl)-N′-(diphenylmethylene)-N-p-tolylacetohydrazide (400mg, 0.91 mmol; Example 63A) and tropinone (190 mg, 1.4 mmol; Aldrich)into the title compound as the trifluoroacetic acid salt: MS (DCI/NH₃)m/z 395.8 (M+NH₄)⁺.

Example 645-[2-(4-chlorophenyl)propyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube with a septum cap was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 1.1 mmol; Example 1A), sodium (30-35% dispersion in paraffin;169 mg, 2.21 mmol; Aldrich), hydroquinone (15.0 mg, 0.100 mmol; Aldrich)and dimethyl sulfoxide (1 mL), and the vessel was evacuated and flushedwith nitrogen (3×). A solution of 1-chloro-4-(prop-1-en-2-yl)benzene(253 mg, 1.66 mmol; Aldrich) in dimethyl sulfoxide (1.5 mL) was addedvia a syringe and the vessel was again evacuated and flushed withnitrogen, and then heated at 100° C. for 72 hours. After the mixture wascooled to room temperature, brine (2 mL) was added and the mixture wasstirred for few minutes. Ethyl acetate (4 mL) was added and mixture wasstirred for several minutes at 40° C. The organic phase was separated,concentrated, and the resulting material was purified by reverse-phaseHPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (m, 1H), 1.41 (d, J=7.5 Hz,3H), 2.05 (m, 3H), 2.25 (s, 3H), 2.42 (s, 3H), 2.55 (m, 1H), 2.69 (m,1H), 3.29 (m, 1H), 4.16 (m, 1H), 4.29 (m, 2H), 4.87 (m 1H), 6.82 (m,3H), 7.18 (m, 3H), 7.30 (d, J=8 Hz, 1H); MS (ESI) m/z 379 (M+H)⁺.

Example 655-(4-isopropenylphenyl)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(200 mg, 0.884 mmol; Example 1A), sodium (30-35% dispersion in paraffin;122 mg, 1.591 mmol; Aldrich) and hydroquinone (9.7 mg, 0.088 mmol;Aldrich) and then sealed with a septum cap. A solution of1-fluoro-4-(prop-1-en-2-yl)benzene (180 mg, 1.326 mmol; Aldrich) indimethyl sulfoxide (1 mL) was introduced through the septum and thevessel was evacuated and backfilled with nitrogen (˜10×). The mixturewas heated at 100° C. for 72 hours. After cooling, the reaction mixturewas diluted with water (5 mL), extracted with dichloromethane, andpurified by reverse-phase HPLC (Phenomenex® Luna® C8(2) 5 min 100 Å AXIAcolumn, 30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm1.78-1.98 (m, 1H), 2.22 (s, 3H), 2.48 (s, 3H), 2.57-2.78 (m, 4H), 2.83(s, 3H), 3.28 (d, J=4.4 Hz, 1H), 4.30 (s, 1H), 5.01 (s, 1H), 5.21 (s,1H), 5.44 (s, 1H), 7.06 (d, J=9.5 Hz, 1H), 7.15-7.21 (m, 1H), 7.22-7.34(m, 3H), 7.57-7.67 (m, 2H); MS (ESI) m/z 343 (M+H).

Example 662,11-dimethyl-5-(3-phenylpropyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (0.014 g, 0.331 mmol; Alfa Aesar), chilled to 0° C., and treatedwith2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (50mg, 0.220 mmol; Example 1A), added in portions. After 5 minutes, the icebath was removed and stirring was continued for 1 hour. The solution waschilled again in an ice bath and (3-bromopropyl)benzene (44 mg, 0.221mmol; Aldrich) was added dropwise. After 10 minutes, the ice bath wasremoved and stirring was continued for 1.5 hours. The reaction mixturewas then diluted with water (10 mL) and extracted with dichloromethane(2×15 mL). The combined organic extracts were dried over magnesiumsulfate, filtered, concentrated in vacuo, and the resulting residue waspurified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in0.1% trifluoroacetic acid, over 15 minutes) to afford the title compoundas the trifluoroacetate salt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.00 (d,J=14.6 Hz, 1H), 1.28-1.52 (m, 2H), 1.61 (s, 1H), 1.93-2.15 (m, 5H),2.52-2.82 (m, 5H), 2.95 (d, J=3.7 Hz, 1H), 3.18 (dd, J=17.6, 4.4 Hz,1H), 3.90-4.16 (m, 2H), 4.35 (s, 1H), 4.97 (s, 1H), 6.98-7.18 (m, 5H),7.29-7.36 (m, 3H); MS (DCI/NH₃) m/z 345 (M+H)⁺.

Example 675-[2-(4-fluorophenoxy)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A flask containing tetrahydrofuran (5.0 mL) was charged with sodiumamide (109 mg, 2.65 mmol; Alfa Aesar), chilled to 0° C., and treatedwith2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(300 mg, 1.326 mmol; Example 1A), added in portions. After 5 minutes,the ice bath was removed and the mixture was heated to 60° C. for 15minutes. The solution was cooled to room temperature and1-(2-bromoethoxy)-4-fluorobenzene (348 mg, 1.591 mmol; Aldrich) wasadded slowly. The reaction mixture was stirred overnight at roomtemperature, then diluted with water (5 mL) and extracted withdichloromethane (2×10 mL). The combined organic extracts were dried overmagnesium sulfate, filtered, concentrated in vacuo, and the resultingresidue was purified by reverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm100 Å AXIA column, 30×75 mm, 10-95% gradient of acetonitrile in 0.1%aqueous trifluoroacetic acid, flow rate 50 mL/minute) to afford thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.79-2.07 (m, 1H), 2.12-2.30 (m, 1H), 2.34-2.50 (m,4H), 2.50-2.66 (m, 1H), 2.93 (s, 3H), 3.02-3.20 (m, 1H), 3.66 (d, J=17.1Hz, 1H), 4.13-4.37 (m, 3H), 4.42-4.58 (m, 2H), 4.93-5.12 (m, 1H),6.61-6.84 (m, 2H), 6.81-7.01 (m, 2H), 7.01-7.14 (m, 1H), 7.31 (s, 1H),7.34-7.43 (m, 1H); MS (ESI) m/z 365 (M+H)⁺.

Example 68(7S,10R)-5-isoquinolin-7-yl-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A 30-mL microwave reaction tube was charged with(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(453 mg, 2.0 mmol; Example 23A), 7-bromoisoquinoline (624 mg, 3.00 mmol;Frontier), bis(tri-t-butylphosphine)palladium(0) (51.1 mg, 0.100 mmol;Aldrich) and anhydrous dioxane (8 mL). The vessel was flushed withnitrogen and sodium tert-butoxide (481 mg, 5.00 mmol; Aldrich) wasadded. After purging the reaction mixture with nitrogen again, it wassealed and heated to 180° C. (Biotage Personal Chemistry, maximum 300 W)with stirring for 30 minutes. The mixture was cooled and quenched withwater, and then extracted with ethyl acetate. The organic phase wasconcentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide)] to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.61-1.73 (m, 1H), 1.94-2.04 (m, 1H), 2.23-2.43(m, 3H), 2.43 (s, 3H), 2.45 (s, 3H), 3.21-3.30 (m, 1H), 3.57-3.63 (m,1H), 4.30 (d, J=5 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H),7.33 (s, 1H), 7.84 (dd, J=9, 2 Hz, 1H), 7.92 (d, J=6 Hz, 1H), 8.10-8.18(m, 2H), 8.50 (d, J=6 Hz, 1H), 9.32 (s, 1H); MS (DCI/NH₃) m/z 354(M+H)⁺.

Example 692,11-dimethyl-5-(phenylsulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(230.8 mg, 1.020 mmol; Example 1A) in tetrahydrofuran (5 mL) was treatedwith potassium tert-butoxide (1 M in tetrahydrofuran; 1.6 mL, 1.6 mmol;Aldrich), and the reaction was stirred for 30 minutes at ambienttemperature. Benzenesulfonyl chloride (291.9 mg, 1.653 mmol; Aldrich)was added and the reaction was stirred for 4 hours. The mixture wasdiluted with water (35 mL) and 1 M NaOH (5 mL) and extracted withdichloromethane (2×35 mL). The combined organic layers were dried oversodium sulfate, filtered, concentrated, and the residue was purified byreverse-phase HPLC (Phenomenex® Luna® Combi-HTS™ C8(2) 5 μm 100 Å 30×75mm column, gradient of 10-95% acetonitrile in 0.1% trifluoroacetic acid,flow rate 50 mL/minute) to afford the title compound as thetrifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.92-1.98(m, 1H), 2.20-2.27 (m, 1H), 2.41 (s, 3H), 2.57-2.62 (s, 1H), 2.76 (br s,1H), 2.94 (s, 3H), 3.37-3.44 (m, 1H), 3.72-3.78 (m, 1H), 4.31-4.35 (m,1H), 4.99-5.00 (m, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.32 (s, 1H), 7.51-7.56(m, 2H), 7.63-7.68 (m, 1H), 7.88-7.91 (m, 2H), 7.98 (d, J=8.7 Hz, 1H);MS (DCI/NH₃) m/z 367 (M+H)⁺. Anal. Calcd. for C₂₁H₂₂N₂O₂S.1.15 TFA: C,56.24; H, 4.69; N, 5.63. Found: C, 56.19; H, 4.70; N, 5.66.

Example 70(7R,10S)-2,11-dimethyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of(7R,10S)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(253.0 mg, 1.118 mmol; Example 19A) and p-toluenesulfonyl chloride(284.1 mg, 490 mmol; Aldrich) was performed as described in Example 69except that the crude material was purified by flash chromatography(silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.49-1.54 (m, 1H), 1.76-1.82 (m, 1H),2.20-2.28 (m, 5H), 2.33 (s, 3H), 2.38 (s, 3H), 2.79 (d, J=17.9 Hz, 1H),3.34-3.39 (m, 1H), 3.54-3.58 (m, 1H), 4.09 (d, J=4.8 Hz, 1H), 7.09 (d,J=8.7 Hz, 1H), 7.20 (s, 1H), 7.25-7.28 (m, 2H), 7.63-7.65 (m, 2H), 7.93(d, J=8.3 Hz, 1H); MS (DCI/NH₃) m/z 381 (M+H)⁺. Anal. Calcd. forC₂₂H₂₄N₂O₂S: C, 69.44; H, 6.36; N, 7.36. Found: C, 69.22; H, 6.52; N,7.27.

Example 71(7S,10R)-2,11-dimethyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of(7S,10R)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(196.1 mg, 0.866 mmol; Example 23A) and p-toluenesulfonyl chloride(199.5 mg, 1.046 mmol, Aldrich) was performed as described in Example 69except that the crude material was purified by flash chromatography(silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.49-1.54 (m, 1H), 1.76-1.82 (m, 1H),2.20-2.28 (m, 5H), 2.33 (s, 3H), 2.38 (s, 3H), 2.79 (d, J=17.9 Hz, 1H),3.34-3.39 (m, 1H), 3.54-3.58 (m, 1H), 4.09 (d, J=4.8 Hz, 1H), 7.09 (d,J=8.7 Hz, 1H), 7.20 (s, 1H), 7.25-7.28 (m, 2H), 7.63-7.65 (m, 2H), 7.93(d, J=8.8 Hz, 1H); MS (DCI/NH₃) m/z 381 (M+H)⁺

Example 725-[(4-fluorophenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(198.4 mg, 0.887 mmol; Example 1A) and 4-fluorobenzenesulfonyl chloride(243.2 mg, 1.250 mmol, Aldrich) was performed as described in Example 69except that it was purified by preparative HPLC (Phenomenex® Luna®Combi-HTS™ C8(2) 5 μm 100 Å AXIA™ 30×75 mm column, gradient of 10-100%acetonitrile in 0.1% trifluoroacetic acid, flow rate 50 mL/minute) toafford the title compound as the trifluoroacetic acid salt: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.95-2.01 (m, 1H), 2.21-2.28 (m, 1H), 2.41 (s,3H), 2.55-2.63 (m, 2H), 3.34-3.43 (m, 4H), 3.71-3.79 (m, 1H), 4.32-4.34(m, 1H), 4.99-5.05 (m, 1H), 7.21-7.33 (m, 4H), 7.95-8.01 (m, 3H); MS(DCI/NH₃) m/z 385 (M+H)⁺. Anal. Calcd. for C₂₁H₂₁FN₂O₂S.1.1 TFA: C,54.65; H, 4.37; N, 5.49; F, 16.02. Found: C, 54.45; H, 4.31; N, 5.49; F,15.94.

Example 735-[(4-chlorophenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(114.1 mg, 0.504 mmol; Example 1A) and 4-chlorobenzenesulfonyl chloride(152.7 mg, 0.723 mmol, Aldrich) was performed as described in Example 69except that the crude material was purified by flash chromatography(silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.49-1.56 (m, 1H), 1.78-1.81 (m, 1H),2.22-2.32 (m, 5H), 2.39 (s, 3H), 2.79 (d, J=17.5 Hz, 1H), 3.34-3.39 (m,1H), 3.53-3.59 (m, 1H), 4.10 (d, J=5.2 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H),7.22 (s, 1H), 7.46-7.51 (m, 2H), 7.73-7.78 (m, 2H), 7.93 (d, J=8.7 Hz,1H); MS (DCI/NH₃) m/z 401 (M+H)⁺. Anal. Calcd. for C₂₁H₂₁ClN₂O₂S.0.4H₂O: C, 61.80; H, 5.38; N, 6.86. Found: C, 61.51; H, 5.02; N, 6.70.

Example 742,11-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(232.1 mg, 1.026 mmol; Example 1A) and (trifluoromethyl)benzenesulfonylchloride (367.9 mg, 1.504 mmol, Aldrich) was performed as described inExample 69 except that the crude material was purified by flashchromatography (silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.64-1.70 (m, 1H),1.90-1.94 (m, 1H), 2.22-2.35 (m, 2H), 2.40 (s, 3H), 2.47 (s, 3H), 2.98(d, J=18.2 Hz, 1H), 3.43-3.53 (m, 1H), 3.78-3.52 (m, 1H), 4.35-4.37 (m,1H), 7.17 (d, J=8.7 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=8.3 Hz, 1H),7.80-7.83 (m, 2H), 7.95-8.01 (m, 2H); MS (DCI/NH₃) m/z 435 (M+H)⁺.

Example 755-[(4-methoxyphenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(219.2 mg, 0.969 mmol; Example 1A) and 4-methoxybenzenesulfonyl chloride(278.5 mg, 1.348 mmol, Aldrich) was performed as described in Example 69except that the crude material was purified by flash chromatography(silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.50-1.55 (m, 1H), 1.77-1.83 (m, 1H),2.20-2.28 (m, 5H), 2.38 (s, 3H), 2.78 (d, J=18.2 Hz, 1H), 3.34-3.39 (m,1H), 3.55-3.58 (m, 1H), 3.79 (s, 3H), 4.09 (d, J=4.8 Hz, 1H), 6.93-6.98(m, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.20 (s, 1H), 7.68-7.74 (m, 2H), 7.94(d, J=8.3 Hz, 1H); MS (DCI/NH₃) m/z 397 (M+H)⁺. Anal. Calcd. forC₂₂H₂₄N₂O₃S.0.55 H₂O: C, 65.02; H, 6.23; N, 6.89. Found: C, 65.15; H,6.18; N, 6.73.

Example 762,11-dimethyl-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(235.2 mg, 1.039 mmol; Example 1A) and4-(trifluoromethoxy)benzenesulfonyl chloride (399.9 mg, 1.534 mmol,Aldrich) was performed as described in Example 69 except that the crudematerial was purified by flash chromatography (silica gel, CH₂Cl₂/CH₃OH10:1) to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.46-1.56 (m, 1H), 1.77-1.87 (m, 1H), 2.18-2.31 (m, 5H), 2.39 (s, 3H),2.79 (d, J=18.2 Hz, 1H), 3.34-3.39 (m, 1H), 3.56-3.59 (m, 1H), 4.10 (d,J=4.8 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.23 (s, 1H), 7.36-7.39 (m, 2H),7.86-7.91 (m, 2H), 7.95 (d, J=8.7 Hz, 1H); MS (DCI/NH₃) m/z 451 (M+H)⁺.Anal. Calcd. for C₂₂H₂₁F₃N₂O₃S: C, 58.66; H, 4.70; N, 6.22; F, 12.65.Found: C, 58.77; H, 4.76; N, 6.18; F, 12.66.

Example 772,11-dimethyl-5-(pyridin-3-ylsulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(216.6 mg, 0.857 mmol; Example 1A) and pyridine-3-sulfonyl chloride(290.2 mg, 1.634 mmol, Astatech) was performed as described in Example69 except that the crude material was purified by flash chromatography(silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.52-1.58 (m, 1H), 1.77-1.83 (m, 1H),2.24-2.30 (m, 5H), 2.39 (s, 3H), 2.82 (d, J=18.0 Hz, 1H), 3.34-3.42 (m,1H), 3.53-3.62 (m, 1H), 4.11 (d, J=5.1 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H),7.23 (s, 1H), 7.50 (ddd, J=8.2, 5.0, 0.7 Hz, 1H), 7.94 (d, J=8.5 Hz,1H), 8.16 (ddd, J=8.2, 2.5, 1.5 Hz, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H),8.91 (dd, J=2.4, 0.7 Hz, 1H); MS (DCI/NH₃) m/z 368 (M+H)⁺. Anal. Calcd.for C₂₀H₂₁N₂O₂S.0.4 H₂O: C, 64.11; H, 5.86; N, 11.22. Found: C, 63.74;H, 5.48; N, 11.03.

Example 7811-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 78A11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A mixture of phenylhydrazine hydrochloride (2.89 g, 19.99 mmol; Aldrich)and tropinone (2.78 g, 19.99 mmol; Aldrich) in ethanol (15 mL) washeated at reflux for 3 hours. The resulting solution was cooled to roomtemperature and the volatiles were removed under vacuum. The residue wastaken up in 7% (w/w) H₂SO₄/dioxane (42 g) and heated at 60° C. undernitrogen for 14 hours. The mixture was cooled to room temperature andconcentrated under vacuum. The residue was dissolved in water (25 mL)and the solution was made basic (pH >9) by addition of 25% NaOH (20 mL).The resulting mixture was extracted with CH₂Cl₂ (2×25 mL) and theextract was concentrated to residue which was purified by flashchromatography (120 g silica eluted with CH₂Cl₂—CH₃OH-14.8 M aqueousNH₄OH, 90:10:1) followed by crystallization from ethyl acetate toprovide the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.56-1.72 (m, 1H), 1.89 (t, J=9.3 Hz, 1H), 2.20-2.34 (m, 2H), 2.36 (s,3H), 2.46 (d, J=16.7 Hz, 1H), 3.25 (dd, J=16.7, 4.8 Hz, 1H), 3.55 (t,J=5.4 Hz, 1H), 4.20 (d, J=5.2 Hz, 1H), 6.90-7.05 (m, 2H), 7.25 (d, J=7.1Hz, 1H), 7.38 (d, J=7.1 Hz, 1H); MS (DCI) m/z 213 (M+H)⁺.

Example 78B11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The product of Example 78A (150 mg, 0.707 mmol) and sodium dispersion inparaffin (30%, 120 mg, 1.566 mmol; Aldrich) were weighed into a 20 mLglass vial with stir bar and septum cap. Dimethyl sulfoxide (2 mL) wasadded, and the mixture was stirred at room temperature under nitrogenfor 20 minutes. A solution of hydroquinone (22 mg, 0.20 mmol; Aldrich)and 2-methyl-5-vinylpyridine (166 mg, 1.39 mmol; InternationalPublication No. WO2001/017968) in dimethyl sulfoxide (0.5 mL) was added,and the mixture was heated at 100° C. under nitrogen for 14 hours. Themixture was cooled to room temperature, diluted with water (40 mL) andextracted with dichloromethane (3×20 mL), then with ethyl acetate (2×20mL). The combined organic phase was concentrated under vacuum, and theresidue was passed through a column of silica gel with dichloromethane(150 mL), then CH₂Cl₂—CH₃OH-14.8 M aqueous NH₄OH, (90:10:1). The productwas further purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD30×100 mm column, flow rate 40 mL/minute, 20-95% gradient ofacetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted topH 10 with ammonium hydroxide) over 20 minutes] to provide the titlecompound (120 mg). This material was taken up in ethanol (5 mL) and asolution of HCl in dioxane (4 M, 0.4 mL) was added. Ethyl acetate (10mL) was added, and the mixture was heated to boiling for 2 minutes, thencooled to room temperature, and finally placed in the freezer tocomplete precipitation. The precipitate was collected by filtration anddried under vacuum to provide the title compound as the dihydrochloridesalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.11-1.23 (m, 1H), 1.74-1.83(m, 1H), 1.90 (dd, J=16.6, 1.0 Hz, 1H), 2.05-2.27 (m, 2H), 2.19 (s, 3H),2.41 (s, 3H), 2.77 (dd, J=16.6, 4.4 Hz, 1H), 2.99-3.17 (m, 2H),3.35-3.44 (m, 1H), 4.14 (d, J=5.1 Hz, 1H), 4.19-4.40 (m, 2H), 7.01 (td,J=7.4, 1.2 Hz, 1H), 7.06-7.14 (m, 2H), 7.24 (dd, J=8.0, 2.2 Hz, 1H),7.34 (d, J=8.1 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H);MS (DCI) m/z 332 (M+H)⁺. Anal. Calc. for C₂₂H₂₅N₃.2HCl.1.2H₂O): C,62.03; H, 6.96; N, 9.86. Found: C, 62.09; H, 7.13; N, 9.84.

Example 7911-methyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 79A 1-(diphenylmethylene)-2-phenylhydrazine

General procedure A was used to convert benzophenone hydrazone (3.42 g,20 mmol; Aldrich) and 1-bromobenzene (3.14 g, 20 mmol; Aldrich) to thetitle compound: MS (DCI/NH₃) m/z 273 (M+H)⁺.

Example 79B 2-(diphenylmethylene)-1-phenethyl-1-phenylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-phenylhydrazine (200 mg, 0.735 mmol; Example79A) and (2-bromoethyl)benzene (1.29 g, 6.9 mmol; Aldrich) to the titlecompound: MS (DCI/NH₃) m/z 391 (M+H)⁺.

Example 79C11-dimethyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-phenethyl-1-phenylhydrazine (276 mg, 1.3 mmol;Example 79B) and tropinone (153 mg, 1.1 mmol; Aldrich) to the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm0.89-1.12 (m, 1H), 1.30-1.52 (m, 2H), 1.63 (s, 1H), 1.97-2.18 (m, 2H),2.29-2.65 (m, 5H), 4.08 (s, 1H), 4.17-4.41 (m, 2H), 4.89 (d, J=3.6 Hz,1H), 6.82 (dd, J=7.1, 2.4 Hz, 2H), 7.14-7.23 (m, 4H), 7.32 (t, J=7.1 Hz,1H), 7.47 (t, J=8.3 Hz, 2H); MS (DCI/NH₃) m/z 317 (M+H)⁺.

Example 8011-methyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoletrifluoroacetate Example 80A2-(diphenylmethylene)-1-(2-methylphenethyl)-1-phenylhydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-phenylhydrazine (200 mg, 0.943 mmol; Example79A) and 1-(2-bromoethyl)-2-methylbenzene (1.46 g, 7.37 mmol; Aldrich)into the title compound: MS (DCI/NH₃) m/z 391 (M+H)⁺.

Example 80B11-methyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoletrifluoroacetate

General procedure C was used to convert2-(diphenylmethylene)-1-(2-methylphenethyl)-1-phenylhydrazine (276 mg,0.707 mmol; Example 80A) and tropinone (148 mg, 1.1 mmol; Aldrich) intothe title compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.00 (d, J=14.6 Hz, 1H), 1.28-1.52 (m, 2H), 1.61 (s, 1H),1.93-2.15 (m, 5H), 2.27-2.63 (m, 4H), 3.04-3.27 (m, 2H), 4.08 (s, 1H),4.17-4.45 (m, 2H), 4.90 (s, 1H), 6.66 (d, J=7.5 Hz, 1H), 6.93-7.04 (m,1H), 7.05-7.22 (m, 3H), 7.28-7.38 (m, 1H), 7.47 (dd, J=7.1, 5.4 Hz, 2H);MS (DCI/NH₃) m/z 331 (M+H)⁺.

Example 815-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The product of Example 78A (150 mg, 0.707 mmol) and sodium dispersion inparaffin (30%, 120 mg, 1.57 mmol; Aldrich) were weighed into a 20 mLglass vial with stir bar and septum cap. Dimethyl sulfoxide (2 mL) wasadded, and the mixture was stirred at room temperature under nitrogenfor 20 minutes. A solution of hydroquinone (22 mg, 0.20 mmol; Aldrich)and p-chlorostyrene (199 mg, 1.44 mmol; Aldrich) in dimethyl sulfoxide(0.5 mL) was added, and the mixture was heated at 100° C. under nitrogenfor 39 hours. The mixture was cooled to room temperature, diluted withwater (40 mL) and saturated brine (10 mL) and extracted withdichloromethane (4×20 mL). The combined organic phase was concentratedunder vacuum, and the residue was passed through a column of silica gelwith dichloromethane (100 mL), then CH₂Cl₂—CH₃OH-14.8 M aqueous NH₄OH,90:10:1) to provide the crude title compound. The product was furtherpurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD 30×100 mmcolumn, flow rate 40 mL/minute, 30-95% gradient of acetonitrile inbuffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 18 minutes] to provide the title compound: ¹HNMR (300 MHz, methanol-d₄) δ ppm 1.17-1.30 (m, 1H), 1.73-1.83 (m, 1H),1.88 (dd, J=16.4, 1.2 Hz, 1H), 2.04-2.29 (m, 2H), 2.20 (s, 3H), 2.73(dd, J=16.8, 4.2 Hz, 1H), 2.95-3.14 (m, 2H), 3.40 (dd, J=7.1, 4.4 Hz,1H), 4.15 (d, J=5.4 Hz, 1H), 4.22 (ddd, J=14.3, 8.1, 6.1 Hz, 1H), 4.32(dt, J=14.7, 6.1 Hz, 1H), 6.78-6.85 (m, 2H), 7.02 (ddd, J=7.9, 7.0, 1.0Hz, 1H), 7.07-7.14 (m, 1H), 7.12-7.16 (m, 2H), 7.37 (dd, J=8.1, 1.0 Hz,1H), 7.40 (dd, J=7.8, 1.0 Hz, 1H); MS (DCI) m/z 351/353 (M+H)⁺.

Example 8211-methyl-5-[2-(2-methyl-1,4,5,6-tetrahydropyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 82A 2-Methyl-5-((trimethylsilyl)ethynyl)pyrimidine

Isopropyl acetate (30 mL) was added to a mixture of5-bromo-2-methylpyrimidine (3 g, 17.3 mmol), copper(I) iodide (0.066 g,0.35 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.243g, 0.35 mmol) in a 100 mL 3-neck flask equipped with a condenser. Theresulting solution was sparged with a stream of nitrogen for 15 minutesand kept under nitrogen during further manipulations.Trimethylsilylacetylene (3.12 mL, 22.5 mmol) and diisopropylamine (4.90mL, 34.7 mmol) were added successively to the reaction solution, and themixture was stirred at room temperature for 30 minutes. The dark mixturewas heated at 60° C. for 15 hours, then cooled to room temperature,diluted with isopropyl acetate (15 mL) and filtered through diatomaceousearth. The filtrate was washed successively with saturated aqueousNaHCO₃ (2×25 mL), 10% aqueous Na₂S₂O₃ (20 mL) and brine, then dried(MgSO₄) and concentrated under vacuum. The dark residue was purified byflash chromatography on silica gel (hexanes-ethyl acetate, gradient from100:0-70:30) to provide the title compound: ¹H NMR (300 MHz, CDCl₃) δppm 0.27 (s, 9H), 2.74 (s, 3H), 8.68 (s, 2H).

Example 82B 5-Ethynyl-2-methylpyrimidine

A solution of the product of example 82A (2.05 g, 10.8 mmol) in methanol(30 mL) was stirred with potassium carbonate (1.49 g, 10.8 mmol) at roomtemperature. After 2 hours, the reaction mixture was filtered, and thefiltrate was concentrated under vacuum to provide the title compoundsuitable for use in the next step: ¹H NMR (300 MHz, methanol-d₄) δ ppm2.69 (s, 3H), 3.34 (s, 1H), 8.75 (s, 2H); MS (ESI) m/z 119 (M+H)⁺.

Example 82C11-methyl-5-[2-(2-methylpyrimidin-5-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The product of Example 78A (178 mg, 0.838 mmol) and sodium dispersion inparaffin (30%, 129 mg, 1.68 mmol; Aldrich) were weighed into a 20 mLglass vial with stir bar and septum cap. Dimethyl sulfoxide (3 mL) wasadded, and the mixture was stirred at room temperature under nitrogenfor 20 minutes. A mixture of hydroquinone (28 mg, 0.26 mmol; Aldrich)and 5-ethynyl-2-methylpyrimidine from Example 82B (121 mg, 1.024 mmol)in dimethyl sulfoxide (1.0 mL) was added, and the reaction was heated at100° C. under nitrogen for 64 hours. The mixture was cooled to roomtemperature, diluted with water (40 mL) and extracted withdichloromethane (4×40 mL), then ethyl acetate (2×40 mL). The combinedorganic phase was concentrated under vacuum, and the residue was passedthrough a column of silica gel with dichloromethane (200 mL), thenCH₂Cl₂—CH₃OH-14.8 M aqueous NH₄OH, 90:10:1) to provide the crude titlecompound. This was further purified by reverse-phase HPLC [WatersXBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40 mL/minute, 20-95%gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide) over 18 minutes] to providethe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.59-1.73 (m,1H), 1.93 (t, J=9.3 Hz, 1H), 2.24-2.36 (m, 2H), 2.41 (s, 3H), 2.68 (s,3H), 2.73 (dd, J=17.0, 1.0 Hz, 1H), 3.42 (dd, J=17.0, 4.4 Hz, 1H),3.59-3.72 (m, 1H), 4.25 (d, J=4.7 Hz, 1H), 6.77 (d, J=14.9 Hz, 1 H),7.15 (td, J=7.5, 1.0 Hz, 1H), 7.24 (td, J=7.6, 1.4 Hz, 1H), 7.48 (d,J=7.5 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.85 (d, J=14.9 Hz, 1H), 8.87 (s,2H).

Example 82D11-methyl-5-[2-(2-methyl-1,4,5,6-tetrahydropyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of the product of Example 82C (9 mg, 0.027 mmol) in methanol(10 mL) was treated with PtO₂ (10 mg). The reaction flask was evacuatedand purged with nitrogen (4 cycles), then with hydrogen (5 cycles), andthe suspension was stirred at room temperature under hydrogen (1 atm)for 40 hours. The flask was evacuated and purged with nitrogen (5cycles) and the mixture was filtered through a pad of diatomaceous earthwith methanol (5 mL) rinse. The filtrate was concentrated under vacuumand the residue was taken up in ethyl acetate (1 mL). A solution ofp-toluenesulfonic acid monohydrate (5.5 mg, 0.029 mmol) in ethyl acetate(0.5 mL) was added, and the mixture was stirred for 30 minutes, thenconcentrated under vacuum. The residual solid was triturated with ethylacetate (0.2 mL) and dried under vacuum to provide the title compound asthe p-toluenesulfonate salt: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.72-1.87 (m, 2H), 1.97-2.09 (m, 2H), 2.14 (s, 2H), 2.15 (s, 1H),2.19-2.31 (m, 1H), 2.35 (s, 3H), 2.41-2.71 (m, 2H), 2.81 (s, 1H), 2.96(s, 2H), 2.99-3.15 (m, 3H), 3.37-3.53 (m, 2H), 3.57-3.69 (m, 1H),4.15-4.29 (m, 2H), 4.29-4.38 (m, J=4.8 Hz, 1H), 5.02-5.13 (m, 1H),7.08-7.26 (m, 4H), 7.45 (t, J=7.7 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.64(d, J=8.3 Hz, 2H); MS (DCI) m/z 337 (M+H)⁺.

Example 8311-methyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (215.2mg, 1.014 mmol; Example 78A) and 4-(trifluoromethyl)benzenesulfonylchloride (349.2 mg, 1.430 mmol, Aldrich) was performed as described inExample 69 except that the crude material was purified by flashchromatography (silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.53-1.60 (m, 1H),1.80-1.89 (m, 1H), 2.20-2.30 (m, 5H), 2.84 (dd, J=18.0, 1.0 Hz, 1H),3.39 (dd, J=18.1, 4.2 Hz, 1H), 3.58-3.62 (m, 1H), 4.14 (d, J=4.8 Hz,1H), 7.23-7.34 (m, 2H), 7.43-7.45 (m, 1H), 7.79-7.82 (m, 2H), 7.98-8.00(m, 2H), 8.08-8.10 (m, 1H); MS (DCI/NH₃) m/z 421 (M+H)⁺. Anal. Calcd.for C₂₁H₁₉F₃N₂O₂S: C, 59.99; H, 4.55; N, 6.66. Found: C, 59.87; H, 4.67;N, 6.68.

Example 842-fluoro-11-methyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 84A 1-(diphenylmethylene)-2-(4-fluorophenyl)hydrazine

General procedure A was used to convert benzophenone hydrazone (1.962 g,10.0 mmol; Aldrich) and 1-bromo-4-fluorobenzene (1.75 g, 10.0 mmol;source) to the title compound. MS (DCI/NH₃) m/z 291 (M+H)⁺.

Example 84B2-(diphenylmethylene)-1-(4-methylphenethyl)-1-(4-fluorophenyl)hydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-(4-fluorophenyl)-hydrazine (200 mg, 0.689 mmol;Example 84A) and 4-methylphenethylbromide (274 mg, 1.37 mmol; Aldrich)to the title compound: MS (DCI/NH₃) 409 m/z (M+H)⁺.

Example 84C2-fluoro-11-methyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoletrifluoroacetate

General procedure C was used to convert2-(diphenylmethylene)-1-(4-methylphenethyl)-1-(4-fluorophenyl)hydrazine(300 mg, 0.734 mmol; Example 84B) and tropinone (153 mg, 1.102 mmol;Aldrich) to the title compound as the trifluoroacetic acid salt: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.12-1.39 (m, 1H) 1.71-1.98 (m, 2H)2.05-2.33 (m, 5H) 2.47 (s, 3H) 2.65 (dd, J=16.46, 4.16 Hz, 1H) 2.88-3.20(m, 2H) 3.32-3.54 (m, 1H) 3.98-4.30 (m, 3H) 6.71 (d, J=8.1 Hz, 2H),6.94-7.03 (m, 2H), 7.08 (s, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.46 (dd,J=9.0, 3.9 Hz, 1H); MS (DCI/NH₃) m/z 349 (M+H)⁺.

Example 852-fluoro-5-[2-(4-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 85A 1-(4-fluorophenethyl)-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (6.0 mL; Aldrich) was charged withsodium amide (0.488 g, 11.89 mmol; Acros) and chilled to 0° C.(4-Fluorophenyl)hydrazine (1.0 g, 7.9 mmol; Aldrich) was added inportions. After 5 minutes the solid had completely dissolved. The icebath was removed and stirring was continued for 1 hour. The solution waschilled again in an ice bath and 1-(2-bromoethyl)-4-fluorobenzene (1.731ml, 8.72 mmol; Aldrich) was added dropwise. After 10 minutes the icebath was removed and stirring was continued for 1.5 hours. The mixturewas poured into water (5 mL). The tetrahydrofuran was removed underreduce pressure and the residue was diluted with water (20 mL). Theaqueous layer was extracted with diisopropyl ether (2×25 mL) and thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated in vacuo to afford the title product which was carriedon without further purification: MS (DCI/NH₃) m/z 248.9 (M+H)⁺.

Example 85B2-fluoro-5-[2-(4-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert1-(4-fluorophenethyl)-1-(4-fluorophenyl)-hydrazine (276 mg, 1.1 mmol;Example 85A) and tropinone (232 mg, 1.7 mmol; Aldrich) into the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm1.79-2.15 (m, 2H), 2.41-2.69 (m, 5H), 3.08 (t, J=6.2 Hz, 2H), 4.11 (s,1H), 4.18-4.36 (m, 2H), 4.80 (d, J=4.8 Hz, 1H), 6.73-6.83 (m, 2H),6.84-6.94 (m, 2H), 6.99-7.17 (m, 2H), 7.32 (dd, J=8.9, 4.2 Hz, 1H); MS(DCI/NH₃) m/z 353 (M+H)⁺.

Example 862-fluoro-5-[2-(3-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 86A2-(diphenylmethylene)-1-(3-fluorophenethyl)-1-(4-fluorophenyl)hydrazine

General procedure B was used to convert1-(diphenylmethylene)-2-(4-fluorophenyl)-hydrazine (200 mg, 0.69 mmol;Example 84A) and 1-(2-bromoethyl)-3-fluorobenzene (280 mg, 1.37 mmol;Aldrich) into the title compound: MS (DCI/NH₃) 413 m/z (M+H)⁺.

Example 86B2-fluoro-5-[2-(3-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

General procedure C was used to convert2-(diphenylmethylene)-1-(3-fluorophenethyl)-1-(4-fluorophenyl)hydrazine(300 mg, 0.727 mmol; Example 86A) and tropinone (152 mg, 1.091 mmol;Aldrich) into the title compound as the trifluoroacetic acid salt. ¹HNMR (300 MHz, CDCl₃) δ ppm 1.02-1.55 (m, 2H), 1.79-2.15 (m, 2H),2.41-2.69 (m, 5H), 3.08 (t, J=6.2 Hz, 2H), 4.11 (s, 1H), 4.18-4.36 (m,2H), 4.80 (d, J=4.8 Hz, 1H), 6.52-6.64 (m, 1H), 6.68-6.79 (m, 1H),6.88-7.07 (m, 3H), 7.23 (dd, J=9.5, 2.4 Hz, 2H).

Example 872-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 87A2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A mixture of 4-bromophenylhydrazine hydrochloride (4.87 g, 21.8 mmol;Aldrich) and tropinone (3.03 g, 21.8 mmol; Aldrich) in 1 M HCl-aceticacid (50 mL) was stirred at 20° C. for 1 hour, then warmed to 60° C. for8.5 hours and cooled to room temperature. The reaction mixture wasconcentrated under vacuum and the residue was purified by flashchromatography (silica gel, eluted with CH₂Cl₂—CH₃OH-14.8 M aqueousNH₄OH (90:10:1)) to provide the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.54-1.71 (m, 1H), 1.88 (t, J=9.2 Hz, 1H), 2.19-2.33(m, 2H), 2.36 (s, 3H), 2.46 (d, J=16.6 Hz, 1H), 3.24 (dd, J=16.8, 4.6Hz, 1H), 3.50-3.60 (m, 1H), 4.17 (d, J=5.1 Hz, 1H), 7.09 (dd, J=8.5, 1.7Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H); MS (DCI) m/z291/293 (MH⁺).

Example 87B2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

2-Bromo-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(228 mg, 0.783 mmol; Example 87A) and sodium dispersion in paraffin(30%, 168 mg, 2.19 mmol; Aldrich) were weighed into a 20 mL glass vialwith stir bar and septum cap. Dimethyl sulfoxide (2.5 mL) was added, andthe mixture was stirred at room temperature under nitrogen for 30minutes. A solution of hydroquinone (52 mg, 0.48 mmol; Aldrich) and4-chlorostyrene (213 mg, 1.54 mmol; Aldrich) in dimethyl sulfoxide (2mL) was added, and the reaction was heated at 105° C. under nitrogen for87 hours. The mixture was cooled to room temperature, diluted with water(100 mL) and extracted with chloroform (3×50 mL). The combined organicphases were washed with brine (30 mL) and concentrated under vacuum. Theresidue was purified by flash chromatography (silica gel, eluted withCHCl₃—CH₃OH-14.8 M aqueous NH₄OH, 100:0:0-90:10:1) to provide the crudetitle compound. This was further purified by reverse-phase HPLC [WatersXBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40 mL/minute, 40-99%gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to providethe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.16-1.30 (m,1H), 1.78 (t, J=9.3 Hz, 1H), 1.90 (d, J=17.0 Hz, 1H), 2.04-2.30 (m, 2H),2.22 (s, 3H), 2.74 (dd, J=17.0, 4.1 Hz, 1H), 2.96-3.11 (m, 2H), 3.43(dd, J=6.4, 4.7 Hz, 1H), 4.15 (d, J=5.1 Hz, 1H), 4.17-4.37 (m, 2H),6.77-6.86 (m, 2H), 7.12-7.16 (m, 2H), 7.19 (dd, J=8.6, 1.9 Hz, 1H), 7.30(d, J=8.5 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H); MS (DCI) m/z 429/431/433(M+H)⁺.

Example 88(7R,10S)-2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the racemic mixture of Example 87B wereseparated by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40 mL/minute) toobtain the title compound as the first eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.14-1.28 (m, 1H), 1.72-1.81 (m, 1H), 1.89 (d,J=16.7 Hz, 1H), 2.07-2.26 (m, 2H), 2.19 (s, 3H), 2.73 (dd, J=16.5, 4.2Hz, 1H), 2.97-3.12 (m, 2H), 3.36-3.44 (m, 1H), 4.11 (d, J=5.2 Hz, 1H),4.22 (ddd, J=14.7, 7.5, 5.9 Hz, 1H), 4.31 (dt, J=14.7, 5.9 Hz, 1H), 6.82(d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.18 (dd, J=8.7, 1.6 Hz, 1H),7.30 (d, J=8.7 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H).

Example 89(7S,10R)-2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the racemic mixture of Example 87B wereseparated by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40 mL/minute) toobtain the title compound as the second-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.16-1.27 (m, 1H), 1.76 (t, J=9.3 Hz, 1H), 1.89(d, J=16.6 Hz, 1H), 2.05-2.25 (m, 2H), 2.19 (s, 3H), 2.73 (dd, J=16.8,3.6 Hz, 1H), 2.99-3.10 (m, 2H), 3.36-3.43 (m, 1H), 4.11 (d, J=4.7 Hz,1H), 4.17-4.35 (m, 2H), 6.82 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H),7.16-7.21 (m, J=8.5, 2.0 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.54 (d, J=1.7Hz, 1H).

Example 902-bromo-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The reaction of2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(320.5 mg, 1.101 mmol; Example 87A) and p-toluenesulfonyl chloride(221.8 mg, 1.163 mmol, Aldrich) was performed as described in Example 69except that the crude material was purified by flash chromatography(silica gel, CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.49-1.54 (m, 1H), 1.77-1.83 (m, 1H),2.19-2.28 (m, 5H), 2.35 (s, 3H), 2.82 (d, J=18.2 Hz, 1H), 3.35-3.41 (m,1H), 3.54-3.59 (m, 1H), 4.11 (d, J=4.8 Hz, 1H), 7.30-7.32 (m, 2H), 7.39(dd, J=8.9, 1.8 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.67-7.70 (m, 2H), 8.00(d, J=8.7 Hz, 1H); MS (DCI/NH₃) m/z 445 (M+H)⁺.

Example 912-methoxy-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 91A2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A suspension of (4-methoxyphenyl)hydrazine hydrochloride (875 mg, 5.0mmol, Aldrich), tropinone (696 mg, 5.0 mmol; Aldrich), and 4 MHCl-dioxane (2.5 mL, 10.0 mmol; Aldrich) in ethanol (10 mL) was heatedto 80° C. for 16 hours. After cooling to room temperature, the reactionmixture was concentrated, basified with 5 N NaOH (aqueous), and thenextracted with ethyl acetate (3×50 mL). The combined organic phases wereconcentrated and the residue was purified by reverse-phase HPLC [WatersXBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-95%gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide)] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.67-1.81 (m, 1H), 1.99(t, J=9 Hz, 1H), 2.25-2.43 (m, 2H), 2.50 (s, 3H), 2.57 (d, J=17 Hz, 1H),3.26-3.34 (m, 1H), 3.68-3.76 (m, 1H), 3.80 (s, 3H), 4.39 (d, J=4 Hz,1H), 6.70 (dd, J=9, 2 Hz, 1H), 6.93 (d, J=2 Hz, 1H), 7.16 (d, J=9 Hz,1H); MS (DCI/NH₃) m/z 243 (M+H)⁺.

Example 91B2-methoxy-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(100 mg, 0.413 mmol; Example 91A) and 2-methyl-5-vinylpyridine (98 mg,0.825 mmol; IBScreen) was performed as described in Example 1B to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.11-1.24 (m,1H), 1.73-1.83 (m, 1H), 1.87 (d, J=16 Hz, 1H), 2.04-2.28 (m, 2H), 2.18(s, 3H), 2.41 (s, 3H), 2.74 (dd, J=17, 4 Hz, 1H), 2.97-3.15 (m, 2H),3.35-3.41 (m, 1H), 3.81 (s, 3H), 4.11 (d, J=5 Hz, 1H), 4.15-4.36 (m,2H), 6.75 (dd, J=9, 2 Hz, 1H), 6.92 (d, J=2 Hz, 1H), 7.09 (d, J=8 Hz,1H), 7.20-7.28 (m, 2H), 7.75 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 362(M+H)⁺.

Example 92(7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(122 mg, 0.503 mmol; Example 91A) and 1-chloro-4-vinylbenzene (140 mg,1.00 mmol, Aldrich) was performed as described in Example 1B to affordthe title compound as a racemic mixture. Individual enantiomers wereobtained by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40 mL/minute) toafford the title compound as the first-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.18-1.30 (m, 1H), 1.74-1.90 (m, 2H), 2.05-2.31(m, 2H), 2.22 (s, 3H), 2.72 (dd, J=16, 4 Hz, 1H), 2.96-3.10 (m, 2H),3.38-3.45 (m, 1H), 3.82 (s, 3H), 4.13-4.34 (m, 3H), 6.77 (dd, J=9, 2 Hz,1H), 6.82 (d, J=8 Hz, 2H), 6.93 (d, J=2 Hz, 1H), 7.14 (d, J=8 Hz, 2H),7.26 (d, J=9 Hz, 1H); MS (DCI/NH₃) m/z 381/383 (M+H)⁺.

Example 93(7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

Purification of the racemic mixture from Example 92 by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine, flow rate 40 mL/minute) afforded the title compound as thesecond-eluting enantiomer: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.18-1.29(m, 1H), 1.74-1.90 (m, 2H), 2.05-2.29 (m, 2H), 2.21 (s, 3H), 2.71 (dd,J=16, 4 Hz, 1H), 2.94-3.12 (m, 2H), 3.37-3.43 (m, 1H), 3.82 (s, 3H),4.12-4.33 (m, 3H), 6.76 (dd, J=9, 2 Hz, 1H), 6.82 (d, J=8 Hz, 2H), 6.93(d, J=2 Hz, 1H), 7.14 (d, J=8 Hz, 2H), 7.26 (d, J=9 Hz, 1H); MS(DCI/NH₃) m/z 381/383 (M+H)⁺.

Example 94(7R,10S)-2-methoxy-11-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(122 mg, 0.503 mmol; Example 91A) and 1-(trifluoromethyl)-3-vinylbenzene(172 mg, 1.00 mmol, Aldrich) was performed as described in Example 1B toafford the title compound as a racemic mixture. Individual enantiomerswere obtained by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40 mL/minute) toafford the title compound as the first-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.10-1.23 (m, 1H), 1.70-1.81 (m, 1H), 1.88 (d,J=17 Hz, 1H), 2.05-2.26 (m, 2H), 2.17 (s, 3H), 2.75 (dd, J=17, 4 Hz,1H), 3.05-3.21 (m, 2H), 3.34-3.40 (m, 1H), 3.81 (s, 3H), 4.10 (d, J=5Hz, 1H), 4.18-4.38 (m, 2H), 6.74 (dd, J=9, 2 Hz, 1H), 6.92 (d, J=2 Hz,1H), 7.11 (d, J=7 Hz, 1H), 7.15 (s, 1H), 7.23 (d, J=9 Hz, 1H), 7.33 (t,J=8 Hz, 1H), 7.41-7.47 (m, 1H); MS (DCI/NH₃) m/z 415 (M+H)⁺.

Example 95(7S,10R)-2-methoxy-11-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

Purification of the racemic mixture from Example 94 by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine, flow rate 40 mL/minute) afforded the title compound as thesecond-eluting enantiomer: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.11-1.23(m, 1H), 1.72-1.82 (m, 1H), 1.89 (d, J=17 Hz, 1H), 2.04-2.27 (m, 2H),2.18 (s, 3H), 2.76 (dd, J=16, 4 Hz, 1H), 3.05-3.21 (m, 2H), 3.35-3.42(m, 1H), 3.81 (s, 3H), 4.12 (d, J=5 Hz, 1H), 4.19-4.39 (m, 2H), 6.75(dd, J=9, 2 Hz, 1H), 6.92 (d, J=2 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.15(s, 1H), 7.23 (d, J=9 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.41-7.47 (m, 1H);MS (DCI/NH₃) m/z 415 (M+H)⁺.

Example 965-[2-(4-chlorophenyl)ethyl]-4-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 96A4-methoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

A suspension of (2-methoxyphenyl)hydrazine hydrochloride (875 mg, 5.0mmol; TCI-US), tropinone (696 mg, 5.0 mmol; Aldrich), and 4M HCl-dioxane(2.5 mL, 10.0 mmol; Aldrich) in ethanol (10 mL) was heated to 80° C. for16 hours. After cooling to room temperature, the reaction mixture wasconcentrated, basified with 5 N NaOH (aqueous), and then extracted withethyl acetate (3×50 mL). The combined organic phase was concentrated andthe residue was purified by reverse-phase HPLC [Waters XBridge™ RP18column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide)] to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.62-1.80 (m, 1H), 1.97 (t, J=9 Hz, 1H),2.24-2.38 (m, 2H), 2.47 (s, 3H), 2.57 (d, J=17 Hz, 1H), 3.25-3.36 (m,1H), 3.65-3.73 (m, 1H), 3.92 (s, 3H), 4.34 (d, J=4 Hz, 1H), 6.59 (d, J=8Hz, 1H), 6.87-6.95 (m, 1H), 6.97-7.04 (m, 1H); MS (DCI/NH₃) m/z 243(M+H)⁺.

Example 96B5-[2-(4-chlorophenyl)ethyl]-4-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of4-methoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (49mg, 2.0 mmol, Example 96A) and 1-chloro-4-vinylbenzene (40 mg, 0.289mmol, Aldrich) was performed as described in Example 1B to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄, with NaOD added) δ ppm1.11-1.23 (m, 1H), 1.69-1.79 (m, 1H), 1.85 (d, J=17 Hz, 1H), 2.07-2.27(m, 5H), 2.73 (dd, J=16, 4 Hz, 1H), 2.93-3.10 (m, 2H), 3.96 (s, 3H),4.05 (d, J=5 Hz, 1H), 4.26-4.39 (m, 1H), 4.44-4.55 (m, 1H), 6.66 (dd,J=7, 1 Hz, 1H), 6.82 (d, J=8 Hz, 2H), 6.90-7.03 (m, 2H), 7.14 (d, J=8Hz, 2H); MS (DCI/NH₃) m/z 381/383 (M+H)⁺.

Example 975-[2-(4-chlorophenyl)ethyl]-1-methyl-2-(trifluoromethoxy)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 97A11-methyl-2-trifluoromethoxy-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of 4-(trifluoromethoxy)phenylhydrazine hydrochloride (1062mg, 5.0 mmol; Maybridge), tropinone (696 mg, 5.0 mmol; Aldrich), andconcentrated sulfuric acid (2.0 mL; J. T Baker) in dioxane (30 mL) washeated to 80° C. for 16 hours. After cooling to room temperature, thereaction mixture was concentrated, basified with 5 N NaOH (aqueous), andthen extracted with ethyl acetate (3×50 mL). The combined organic phasewas concentrated and the residue was purified by reverse-phase HPLC[Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute,20-95% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.58-1.73 (m, 1H),1.90 (t, J=9 Hz, 1H), 2.25-2.34 (m, 2H), 2.37 (s, 3H), 2.48 (dd, J=17, 1Hz, 1H), 3.21-3.28 (m, 1H), 3.53-3.60 (m, 1H), 4.20 (d, J=5 Hz, 1H),6.91 (dt, J=9, 1 Hz, 1H), 7.24-7.31 (m, 2H); MS (DCI/NH₃) m/z 297(M+H)⁺.

Example 97B5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethoxy)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of11-methyl-2-trifluoromethoxy-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(50 mg, 0.169 mmol; Example 97A) and 1-chloro-4-vinylbenzene (45 mg,0.339 mmol; Aldrich) was performed as described in Example 1B to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.21-1.32 (m,1H), 1.73-1.83 (m, 1H), 1.90 (d, J=17 Hz, 1H), 2.07-2.30 (m, 2H), 2.21(s, 3H), 2.74 (dd, J=17, 4 Hz, 1H), 2.98-3.13 (m, 2H), 3.38-3.44 (m,1H), 4.14 (d, J=5 Hz, 1H), 4.20-4.41 (m, 2H), 6.84 (d, J=8 Hz, 2H), 7.00(d, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 2H), 7.30 (s, 1H), 7.40 (d, J=9 Hz,1H); MS (DCI/NH₃) m/z 435/437 (M+H)⁺.

Example 985-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 98A11-methyl-2-(trifluoromethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of 4-(trifluoromethyl)phenyl)hydrazine (1.5 g, 8.52 mmol;Aldrich) and tropinone (1.19 g, 8.52 mmol) in 7% sulfuric acid indioxane (50 mL) was heated to 100° C. overnight. Water (100 mL) wasadded and the solution was basified (to ˜pH 12) by the addition of 4 Maqueous NaOH. The aqueous solution was extracted with dichloromethane(3×75 mL) and the combined extracts were concentrated in vacuo andpurified by flash chromatography (40 g silica gel, 0-100%CH₂Cl₂/CH₃OH/14.8 M aqueous NH₄OH (78:20:2) in CH₂Cl₂ over 25 minutes)to afford the title compound. ¹H NMR (300 MHz, methanol-d₄) δ ppm1.93-2.15 (m, 1H), 2.22-2.38 (m, 1H), 2.54-2.72 (m, 2H), 2.93-3.14 (m,2H), 3.37 (s, 3H), 4.33 (s, 1H), 5.04-5.23 (m, 1H), 7.34-7.46 (m, 1H),7.46-7.61 (m, 1H), 7.88 (s, 1H); MS (ESI)⁺ m/z 281 (M+H)⁺.

Example 98B5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A reaction tube was charged with11-methyl-2-(trifluoromethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(280 mg, 0.999 mmol; Example 98A), sodium (30-35% dispersion inparaffin; 91 mg, 1.193 mmol; Aldrich) and hydroquinone (11.00 mg, 0.100mmol; Aldrich) and then sealed with a septum cap. Dimethyl sulfoxide (1mL) and 1-chloro-4-vinylbenzene (277 mg, 1.998 mmol; Aldrich) wereintroduced through the septum and the vessel was evacuated andbackfilled with nitrogen (˜10×). The mixture was heated at 100° C. for72 hours. After cooling, the reaction mixture was diluted with water (5mL), extracted with dichloromethane, concentrated, and purified byreverse-phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column,30×75 mm, 10-95% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid, flow rate 50 mL/minute) to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.30-1.60 (m, 1H), 1.96-2.16 (m, 1H), 2.26 (d, J=17.6 Hz, 1H),2.30-2.53 (m, 2H), 2.65 (s, 4H), 2.94-3.20 (m, 3H), 3.98 (s, 1H), 4.32(d, J=22.0 Hz, 1H), 4.40-4.62 (m, 1H), 6.74-6.98 (m, 2H), 7.19 (d, J=8.5Hz, 2H), 7.46 (d, J=6.8 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.86 (s, 1H);MS (ESI) m/z 419 (M+H)⁺.

Example 992-isopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 99A2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of (4-isopropylphenyl)hydrazine hydrochloride (930 mg, 5.0mmol; Aldrich), tropinone (696 mg, 5.0 mmol; Aldrich), and 4 MHCl-dioxane (2.5 mL, 10.0 mmol; Aldrich) in ethanol (10 mL) was heatedto 80° C. for 16 hours. After cooling to room temperature, the reactionmixture was concentrated, basified with 5 N NaOH (aqueous), and thenextracted with ethyl acetate (3×50 mL). The combined organic phases wereconcentrated and the residue was purified by reverse-phase HPLC [WatersXBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-95%gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide)] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.26 (s, 3H), 1.28 (s,3H), 1.57-1.71 (m, 1H), 1.90 (t, J=10 Hz, 1H), 2.22-2.35 (m, 2H), 2.37(s, 3H), 2.45 (d, J=15 Hz, 1H), 2.89-3.00 (m, 1H), 3.24 (dd, J=17, 4 Hz,1H), 3.54 (t, J=5 Hz, 1H), 4.20 (d, J=5 Hz, 1H), 6.92 (dd, J=9, 1 Hz,1H), 7.17 (d, J=9 Hz, 1H), 7.22 (s, 1H); MS (DCI/NH₃) m/z 255 (M+H)⁺.

Example 99B2-isopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(85 mg, 0.334 mmol; Example 99A) and 2-methyl-5-vinylpyridine (80 mg,0.668 mmol; IBScreen) was performed as described in Example 1B to affordthe title compound: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 1.35 (d, J=7 Hz,6H), 1.41-1.50 (m, 1H), 1.98 (t, J=11 Hz, 1H), 2.28 (d, J=17 Hz, 1H),2.36-2.43 (m, 1H), 2.44 (s, 3H), 2.55-2.77 (m, 4H), 2.99 (t, J=7 Hz,2H), 3.03-3.12 (m, 1H), 4.16-4.25 (m, 3H), 5.10 (d, J=5 Hz, 1H), 6.92(d, J=8 Hz, 1H), 7.09 (d, J=6 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.50 (d,J=8 Hz, 1H), 7.53 (s, 1H), 8.16 (s, 1H); MS (DCI/NH₃) m/z 374 (M+H)⁺.

Example 100(7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(127 mg, 0.499 mmol; Example 99A) and 1-chloro-4-vinylbenzene (138 mg,0.999 mmol, Aldrich) was performed as described in Example 1B to affordthe title compound as a racemic mixture. Individual enantiomers wereobtained by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40 mL/minute) toafford the title compound as the first-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.18-1.28 (m, 1H), 1.30 (d, J=7 Hz, 6H),1.74-1.88 (m, 2H), 2.05-2.28 (m, 2H), 2.20 (s, 3H), 2.70 (dd, J=16, 4Hz, 1H), 2.92-3.12 (m, 3H), 3.36-3.42 (m, 1H), 4.13-4.33 (m, 3H), 6.82(d, J=8 Hz, 2H), 7.02 (dd, J=8, 2 Hz, 1H), 7.14 (d, J=8 Hz, 2H), 7.25(d, J=2 Hz, 1H), 7.29 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 393 (M+H)⁺.

Example 101(7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

Purification of the racemic mixture from Example 100 by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine, flow rate 40 mL/minute) afforded the title compound as thesecond-eluting enantiomer: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.17-1.28(m, 1H), 1.30 (d, J=7 Hz, 6H), 1.74-1.88 (m, 2H), 2.04-2.28 (m, 2H),2.19 (s, 3H), 2.69 (dd, J=16, 4 Hz, 1H), 2.92-3.12 (m, 3H), 3.35-3.39(m, 1H), 4.10-4.34 (m, 3H), 6.82 (d, J=8 Hz, 2H), 7.02 (dd, J=8, 2 Hz,1H), 7.14 (d, J=8 Hz, 2H), 7.24 (d, J=1 Hz, 1H), 7.28 (d, J=8 Hz, 1H);MS (DCI/NH₃) m/z 393 (M+H)⁺.

Example 1022-cyclopropyl-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-bromo-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(340.0 mg, 0.763 mmol; Example 90) in toluene (8 mL) and water (0.4 mL)was treated with cyclopropylboronic acid (91.7 mg, 1.068 mmol; Aldrich),potassium phosphate (530.9 mg, 2.74 mmol), tricyclohexylphosphine (25.3mg, 0.090 mmol; Aldrich) and palladium(II) acetate (11.0 mg, 0.049 mmol;Aldrich). The reaction was purged with nitrogen for 15 minutes, and thenheated to 100° C. for 18 hours. The resulting mixture was diluted withwater (35 mL) and extracted with dichloromethane (3×35 mL). The combinedorganic layers were dried over sodium sulfate, filtered andconcentrated, and the residue was purified by silica gel chromatography(CH₂Cl₂/CH₃OH 10:1) to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 0.65-0.70 (m, 2H), 0.91-0.97 (m, 2H), 1.49-1.54 (m,1H), 1.76-1.82 (m, 1H), 1.93-2.01 (m, 1H), 2.20-2.28 (m, 5H), 2.33 (s,3H), 2.78 (d, J=17.9 Hz, 1H), 3.34-3.38 (m, 1H), 3.54-3.59 (m, 1H), 4.10(d, J=4.8 Hz, 1H), 7.01 (dd, J=8.7, 1.6 Hz, 1H), 7.11 (d, J=1.2 Hz, 1H),7.26-7.28 (m, 2H), 7.62-7.65 (m, 2H), 7.93 (d, J=8.7 Hz, 1H); MS(DCI/NH₃) m/z 407 (M+H)⁺.

Example 1032-cyclopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 103A2-cyclopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-cyclopropyl-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(271.2 mg, 0.667 mmol; Example 102) in methanol (5 mL) was treated withpotassium hydroxide (473.6 mg, 7.34 mmol). The reaction mixture washeated to reflux for 19 hours, then diluted with water (35 mL) andextracted with dichloromethane (3×35 mL). The combined organic layerswere washed with brine (25 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 0.60-0.65 (m, 2H), 0.84-0.91 (m, 2H), 1.59-1.69 (m,1H), 1.86-2.00 (m, 2H), 2.26-2.48 (m, 6H), 3.20-3.27 (m, 1H), 3.54-3.56(m, 1H), 4.19 (d, J=4.8 Hz, 1H), 6.79 (dd, J=8.3, 1.6 Hz, 1H), 7.10-7.15(m, 2H); MS (DCI/NH₃) m/z 253 (M+H)⁺.

Example 103B2-cyclopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of2-cyclopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(66.0 mg, 0.262 mmol; Example 103A) in dimethyl sulfoxide (2 mL) wastreated with 2-methyl-5-vinylpyridine (91.8 mg, 0.770 mmol;International Publication No. WO2001/017968), hydroquinone (8.8 mg,0.080 mmol; Aldrich) and sodium dispersion in paraffin (30%; 31.9 mg,0.416 mmol; Aldrich). The reaction was purged with nitrogen and heatedto 110° C. for 19 hours under nitrogen. The mixture was diluted withmethanol (10 mL), filtered, concentrated in vacuo, and purified byreverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flowrate 40 mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] toafford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 0.62-0.66(m, 2H), 0.85-0.94 (m, 2H), 1.15-1.21 (m, 1H), 1.75-1.90 (m, 2H),1.96-2.00 (m, 1H), 2.16-2.23 (m, 4H), 2.41 (s, 3H), 2.62-2.42 (m, 2H),3.00-3.09 (m, 2H), 3.37-3.39 (m, 1H), 4.12 (d, J=4.8 Hz, 1H), 4.23-4.33(m, 2H), 6.88 (dd, J=8.5, 1.7 Hz, 1H), 7.08-7.13 (m, 2H), 7.20-7.25 (m,2H), 7.74 (d, J=2.0 Hz, 1H); MS (DCI/NH₃) m/z 372 (M+H)⁺.

Example 1042-tert-butyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 104A2-tert-butyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A suspension of (4-tert-butylphenyl)hydrazine hydrochloride (1000 mg,5.0 mmol; Aldrich), tropinone (696 mg, 5.0 mmol; Aldrich), and 4 MHCl-dioxane (2.5 mL, 10.0 mmol; Aldrich) in ethanol (10 mL) was heatedto 80° C. for 16 hours. After cooling to room temperature, the reactionmixture was concentrated, basified with 5 N NaOH (aqueous), and thenextracted with ethyl acetate (3×50 mL). The combined organic phase wasconcentrated and the residue was purified by reverse-phase HPLC [WatersXBridge™ RP18 column, 5 m, 30×100 mm, flow rate 40 mL/minute, 20-95%gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide)] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.36 (s, 9H), 1.61-1.74(m, 1H), 1.93 (t, J=9 Hz, 1H), 2.25-2.36 (m, 2H), 2.41 (s, 3H), 2.48 (d,J=17 Hz, 1H), 3.21-3.29 (m, 1H), 3.56-3.63 (m, 1H), 4.26 (d, J=4 Hz,1H), 7.10-7.15 (m, 1H), 7.16-7.21 (m, 1H), 7.38 (d, J=1 Hz, 1H); MS(DCI/NH₃) m/z 269 (M+H)⁺.

Example 104B2-tert-butyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-tert-butyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(62 mg, 0.522 mmol, Example 104A) and 2-methyl-5-vinylpyridine (80 mg,0.668 mmol, IBScreen) was performed according to the procedure describedin Example 1B to afford the title compound: ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.12-1.24 (m, 1H), 1.37 (s, 9H), 1.76-1.92 (m, 2H),2.05-2.28 (m, 2H), 2.19 (s, 3H), 2.41 (s, 3H), 2.74 (dd, J=16, 4 Hz,1H), 2.98-3.14 (m, 2H), 3.39 (dd, J=7, 4 Hz, 1H), 4.15 (d, J=5 Hz, 1H),4.17-4.37 (m, 2H), 7.10 (d, J=8 Hz, 1H), 7.18-7.29 (m, 3H), 7.40 (d, J=1Hz, 1H), 7.73 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 388 (M+H)⁺.

Example 1052-tert-butyl-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-tert-butyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(134 mg, 0.499 mmol, Example 104A) and 1-chloro-4-vinylbenzene (138 mg,0.999 mmol, Aldrich) was performed according to the procedure describedin Example 1B to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.39-1.44 (m, 1H), 1.45 (s, 9H), 1.97 (t, J=11 Hz,1H), 2.26 (d, J=17 Hz, 1H), 2.35-2.44 (m, 1H), 2.52-2.61 (m, 1H), 2.64(s, 3H), 2.93-3.04 (m, 2H), 4.14-4.18 (m, 1H), 4.21 (t, J=7 Hz, 2H),5.12 (d, J=5 Hz, 1H), 6.84 (d, J=8 Hz, 2H), 7.17 (d, J=8 Hz, 2H), 7.51(s, 2H), 7.76 (s, 1H); MS (DCI/NH₃) m/z 407 (M+H)⁺.

Example 1062-(4-chlorophenyl)-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 106A2-bromo-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A suspension of sodium (76 mg, 0.99 mmol, 30% dispersion in paraffinwax, Aldrich),2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(160 mg, 0.55 mmol; Example 87A) and 2-methyl-5-vinylpyridine (118 mg,0.99 mmol; International Publication No. WO2001/017968) in dimethylsulfoxide (2.5 mL) was degassed with nitrogen several times. Thereaction mixture was stirred at 110° C. for 18 hours. The residue wasdiluted with aqueous sodium carbonate (1.0 M, 60 mL) and extracted withchloroform-isopropanol (4:1, 2×30 mL). The combined organic extractswere dried (sodium sulfate), concentrated under vacuum, and the residuewas purified by preparative HPLC [Waters XBridge™ RP18 column, 5 μm,30×100 mm, flow rate 40 mL/minute, 15-95% gradient of acetonitrile inbuffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide)] to afford the title compound: ¹H NMR (500 MHz,methanol-d₄) δ ppm 1.11-1.24 (m, 1H), 1.74-1.81 (m, 1H), 1.89-1.96 (m,1H), 2.10-2.31 (m, 2H), 2.19 (s, 3H), 2.42-2.43 (s, 3H), 2.78 (dd,J=16.6, 3.2 Hz, 1H), 3.00-3.13 (m, 2H), 4.09-4.14 (m, 1H), 4.20-4.29 (m,1H), 4.34 (dt, J=14.7, 5.9 Hz, 1H), 7.08-7.13 (m, 1H), 7.15-7.20 (m,2H), 7.22-7.28 (m, 2H), 7.51-7.56 (m, 1H), 7.76 (d, J=1.8 Hz, 1H); MS(APCI) m/z 410/412 (M+H)⁺.

Example 106B2-(4-chlorophenyl)-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A suspension of the product of Example 106A (22 mg, 0.054 mmol),4-chlorophenylboronic acid (9.2 mg, 0.059 mmol; Aldrich),dichlorobis(triphenylphosphine)palladium (II) (1.9 mg, 2.7 μmol;Aldrich)) and 1.0 M aqueous sodium carbonate (0.54 mL, 0.13 mmol) in2-propanol (1.5 mL) was purged with nitrogen and stirred at 100° C. forone hour. The reaction mixture was cooled and filtered through a glassmicrofiber frit, rinsing with 2-propanol (70% aqueous solution). Theresulting mixture was purified by preparative HPLC [Waters XBridge™ RP18column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 30-99% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide)] to afford the title compound: ¹H NMR (500MHz, methanol-d₄) δ ppm 1.20 (ddd, J=13.0, 9.2, 6.6 Hz, 1H), 1.78-1.86(m, 1H), 1.91 (d, J=16.5 Hz, 1H), 2.09-2.27 (m, 2H), 2.20 (s, 3H), 2.41(s, 3H), 2.78 (dd, J=16.5, 3.7 Hz, 1H), 3.04-3.19 (m, 2H), 3.41 (dd,J=7.3, 4.6 Hz, 1H), 4.20 (d, J=5.5 Hz, 1H), 4.25-4.32 (m, 1H), 4.34-4.42(m, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.27 (dd, J=7.9, 2.1 Hz, 1H), 7.34-7.45(m, 4H), 7.58-7.65 (m, 3H), 7.78 (d, J=1.8 Hz, 1H); MS (APCI) m/z 442(M+H)⁺.

Example 1072-(4-chlorophenyl)-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of the product of Example 87B (30 mg, 0.070 mmol) and4-chlorophenylboronic acid (12 mg, 0.077 mmol; Aldrich) was performedaccording to the procedure described in Example 106B to provide thetitle compound: ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.20-1.30 (m, 1H),1.77-1.84 (m, 1H), 1.88 (d, J=16.8 Hz, 1H), 2.09-2.17 (m, 1H), 2.21 (s,3H), 2.21-2.28 (m, 1H), 2.74 (dd, J=16.8, 3.7 Hz, 1H), 2.99-3.15 (m,2H), 3.37-3.42 (m, J=7.3, 4.3 Hz, 1H), 4.20 (d, J=5.5 Hz, 1H), 4.22-4.29(m, J=14.3, 8.2, 5.8 Hz, 1H), 4.30-4.38 (m, J=14.6, 6.0, 6.0 Hz, 1H),6.85 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 7.35-7.48 (m, 4H),7.60-7.66 (m, 3H); MS (DCI/NH₃) m/z 461 (M+H)⁺.

Example 10811-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 108A11-methyl-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-bromo-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(90 mg, 0.31 mmol; Example 87A) and 3-(trifluoromethyl)phenylboronicacid (65 mg, 0.34 mmol; Aldrich) was performed according to theprocedure described in Example 106B to afford the title compound: ¹H NMR(500 MHz, methanol-d₄) δ ppm 1.62-1.73 (m, 1H), 1.93-1.99 (m, 1H),2.27-2.37 (m, 2H), 2.40 (s, 3H), 2.50 (d, J=16.8 Hz, 1H), 3.24-3.35 (m,1H), 3.57-3.61 (m, 1H), 4.32 (d, J=4.9 Hz, 1H), 7.31-7.35 (m, 1H),7.36-7.39 (m, 1H), 7.52-7.62 (m, 2H), 7.68 (d, J=1.2 Hz, 1H), 7.86-7.91(m, 2H); MS (APCI) m/z 357 (M+H)⁺.

Example 108B11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of11-methyl-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(40 mg, 0.11 mmol; Example 108A) and 2-methyl-5-vinylpyridine (24 mg,0.20 mmol; International Publication No. WO2001/017968) was performed asdescribed in Example 106A to afford the title compound: ¹H NMR (500 MHz,methanol-d₄) δ ppm 1.23 (ddd, J=13.2, 9.1, 6.7 Hz, 1H), 1.81-1.91 (m,1H), 1.96 (d, J=16.5 Hz, 1H), 2.11-2.22 (m, 1H), 2.22-2.30 (m, 1H), 2.25(s, 3H), 2.42 (s, 3H), 2.82 (dd, J=16.2, 2.7 Hz, 1H), 3.05-3.18 (m, 2H),3.47 (dd, J=6.9, 4.4 Hz, 1H), 4.25-4.33 (m, 2H), 4.35-4.44 (m, 1H), 7.12(d, J=7.9 Hz, 1H), 7.29 (dd, J=7.9, 2.1 Hz, 1H), 7.39-7.48 (m, 2H),7.55-7.64 (m, 2H), 7.71 (d, J=1.5 Hz, 1H), 7.78 (d, J=1.8 Hz, 1H),7.87-7.93 (m, 2H); MS (APCI) m/z 476 (M+H)⁺.

Example 1095-[2-(4-chlorophenyl)ethyl]-11-methyl-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(30 mg, 0.07 mmol; Example 87B) and 3-(trifluoromethyl)phenylboronicacid (15 mg, 0.08 mmol; Aldrich) was performed according to theprocedure described in Example 106B to afford the title compound: ¹H NMR(500 MHz, methanol-d₄) δ ppm 1.21-1.29 (m, 1H), 1.78-1.85 (m, 1H), 1.88(d, J=16.5 Hz, 1H), 2.09-2.17 (m, 1H), 2.19-2.28 (m, 1H), 2.21 (s, 3H),2.74 (dd, J=16.2, 3.4 Hz, 1H), 3.02-3.15 (m, 2H), 3.40 (dd, J=7.3, 4.6Hz, 1H), 4.22 (d, J=5.2 Hz, 1H), 4.24-4.31 (m, 1H), 4.32-4.39 (m, 1H),6.83-6.88 (m, 2H), 7.14-7.17 (m, 2H), 7.38-7.44 (m, 1H), 7.47-7.51 (m,1H), 7.54-7.64 (m, 2H), 7.70 (d, J=1.5 Hz, 1H), 7.88-7.94 (m, 2H); MS(DCI/NH₃) m/z 495 (M+H)⁺.

Example 11011-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-pyridin-3-yl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-bromo-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(14.2 mg, 0.035 mmol; Example 106A) and pyridine-3-boronic acid (4.7 mg,0.038 mmol; Aldrich) was performed according to the procedure describedin Example 106B to provide the title compound: ¹H NMR (500 MHz,methanol-d₄) δ ppm 1.21 (ddd, J=13.0, 9.1, 6.6 Hz, 1H), 1.79-1.88 (m,1H), 1.94 (d, J=16.5 Hz, 1H), 2.10-2.19 (m, 1H), 2.19-2.29 (m, 1H), 2.21(s, 3H), 2.42 (s, 3H), 2.80 (dd, J=16.3, 3.8 Hz, 1H), 3.05-3.19 (m, 2H),3.42 (dd, J=7.3, 4.6 Hz, 1H), 4.24 (d, J=5.2 Hz, 1H), 4.26-4.34 (m, 1H),4.35-4.44 (m, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.29 (dd, J=7.9, 2.1 Hz, 1H),7.39-7.43 (m, 1H), 7.46-7.52 (m, 2H), 7.72-7.80 (m, 2H), 8.12 (ddd,J=8.1, 2.0, 1.8 Hz, 1H), 8.45 (dd, J=4.9, 1.5 Hz, 1H), 8.83 (d, J=2.1Hz, 1H); MS (APCI) m/z 409 (M+H)⁺.

Example 1115-[2-(4-chlorophenyl)ethyl]-11-methyl-2-pyridin-3-yl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(30 mg, 0.07 mmol; Example 87B) and pyridine-3-boronic acid (9.4 mg,0.077 mmol; Aldrich) was performed according to the procedure describedin Example 106B to provide the title compound: ¹H NMR (500 MHz,methanol-d₄) δ ppm 1.25 (ddd, J=13.1, 9.0, 6.6 Hz, 1H), 1.75-1.85 (m,1H), 1.89 (d, J=16.5 Hz, 1H), 2.10-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.21(s, 3H), 2.75 (dd, J=16.6, 3.5 Hz, 1H), 3.02-3.15 (m, 2H), 3.40 (dd,J=7.2, 4.7 Hz, 1H), 4.22 (d, J=5.2 Hz, 1H), 4.24-4.31 (m, 1H), 4.32-4.41(m, 1H), 6.85 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 7.38-7.44 (m,1H), 7.48-7.52 (m, 2H), 7.72 (d, J=1.5 Hz, 1H), 8.13 (dt, J=7.9, 1.8 Hz,1H), 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.83 (d, J=1.8 Hz, 1H); MS (DCI/NH₃)m/z 428 (M+H)⁺.

Example 11211-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-(1H-pyrazol-4-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 112A11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-(1-trityl-1H-pyrazol-4-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The coupling of2-bromo-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(33 mg, 0.08 mmol; Example 106A) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole (39mg, 0.09 mmol; as prepared in Japan Patent No. 200523207) was performedaccording to the procedure described in Example 106B to provide thetitle compound: ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.16 (ddd, J=13.0,9.3, 6.1 Hz, 1H), 1.73-1.82 (m, 1H), 1.89 (d, J=16.8 Hz, 1H), 2.06-2.15(m, 1H), 2.16-2.23 (m, 1H), 2.17 (s, 3H), 2.40 (s, 3H), 2.75 (dd,J=16.3, 3.5 Hz, 1H), 3.00-3.13 (m, 2H), 3.38 (dd, J=6.9, 4.7 Hz, 1H),4.14 (d, J=5.5 Hz, 1H), 4.18-4.27 (m, 1H), 4.28-4.37 (m, 1H), 7.07-7.13(m, 2H), 7.18-7.23 (m, 6H), 7.29-7.33 (m, 3H), 7.33-7.38 (m, 8H), 7.50(d, J=1.2 Hz, 1H), 7.68 (s, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.94 (s, 1H);MS (APCI) m/z 640 (M+H)⁺.

Example 112B11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-(1H-pyrazol-4-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

A solution of11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-(1-trityl-1H-pyrazol-4-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(25 mg, 0.039 mmol; Example 112A) in a solvent mixture of methanol (1.0mL) and methylene chloride (1.0 mL) at 0° C. was treated withtrifluoroacetic acid (2.0 mL) and the mixture was allowed to warm toambient temperature. After stirring for 3 hours, the reaction mixturewas concentrated under vacuum and the residue was dissolved in dimethylsulfoxide (2.0 mL) and purified by reverse-phase HPLC [Waters XBridge™RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 35-99% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide)] to afford the title compound: ¹H NMR (500MHz, methanol-d₄) δ ppm 1.18 (ddd, J=12.6, 9.1, 6.7 Hz, 1H), 1.77-1.84(m, 1H), 1.89 (d, J=16.5 Hz, 1H), 2.08-2.16 (m, 1H), 2.19 (s, 3H),2.19-2.26 (m, 1H), 2.41 (s, 3H), 2.76 (dd, J=16.8, 3.1 Hz, 1H),3.02-3.16 (m, 2H), 3.39 (dd, J=7.0, 4.3 Hz, 1H), 4.17 (d, J=5.2 Hz, 1H),4.20-4.29 (m, 1H), 4.30-4.38 (m, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.25 (dd,J=7.9, 2.1 Hz, 1H), 7.34 (s, 2H), 7.61 (s, 1H), 7.78 (d, J=1.8 Hz, 1H),7.91 (s, 2H); MS (APCI) m/z 398 (M+H)⁺.

Example 113(5aS,7S,10R,10aR)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole

A solution of(7S,10R)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(274 mg, 0.79 mmol, Example 8) in trifluoroacetic acid (5 mL) waschilled to −15° C. (ice/salt bath) under nitrogen. A solution of sodiumcyanotrihydroborate (199 mg, 3.17 mmol; Aldrich) in methanol (2 mL) wasadded dropwise (˜15 minute, gas formation!), and then the reaction wasallowed to warm slowly to room temperature. After 2 hours at roomtemperature, methanol (10 mL) was added and the mixture was concentratedin vacuo. The residue was diluted with dichloromethane (50 mL) andwashed with saturated aqueous solution of sodium bicarbonate (30 mL),followed by brine (30 mL), and dried over magnesium sulfate andconcentrated. The resulting material was purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.67 (m, 1H), 1.86 (m, 1H),2.08 (m, 1H), 2.25 (s, 3H), 2.42 (m, 3H), 2.72 (s, 3H), 2.83 (s, 3H),3.04 (m, 3H), 3.30 (m, 2H), 3.54 (m, 1H), 3.85 (m, 2H), 6.62 (d, J=8 Hz,1H), 7.00 (m, 2H), 7.85 (d, J=8 Hz, 1H), 8.43 (dd, J=2, 8 Hz, 1H), 8.65(s, 1H); MS (ESI) m/z 348 (M+H)⁺.

Example 1142,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indoleExample 114A2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

In a 100 mL round-bottom flask were combined p-tolylhydrazinehydrochloride (1.58 g, 10 mmol; Aldrich), pseudopelletierinehydrochloride (2.0 g, 10.5 mmol; Acros), and concentrated sulfuric acid(5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for2.5 hours, then cooled to room temperature. The solvent was decanted,and the residue was dissolved in water (20 mL) and basified with solidpotassium carbonate to pH ˜12. This solution was extracted withdichloromethane (3×50 mL), and the combined organic phases were driedover magnesium sulfate. After removing the solvent under vacuum, theresulting solid was recrystallized from ether to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.21-1.41 (m, 2H),1.60-1.71 (m, 2H), 1.90-2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H),2.42-2.52 (m, 1H), 3.16-3.27 (m, 2H), 4.09 (t, J=3 Hz, 1H), 6.86 (dd,J=8, 1 Hz, 1H), 7.10 (s, 1H), 7.17 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 241(M+H)⁺.

Example 114B2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

A reaction flask with a septum cap was charged with 30% sodium metaldispersion in paraffin wax (0.30 g, 4.0 mmol; Aldrich) and a solution of2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(0.48 g, 2.0 mmol; Example 114A) in dimethyl sulfoxide (4 mL). Thevessel was sealed, flushed with nitrogen, and stirred for 10 minutes. Asolution of 2-methyl-5-vinylpyridine (0.238 g, 2.0 mmol; prepared asdescribed in International Publication No. WO 2001017968) andhydroquinone (0.072 g, 0.66 mmol; Aldrich) in anhydrous dimethylsulfoxide (1.5 mL) was added and the reaction was heated at 100° C. for72 hours. After cooling the mixture to room temperature, it was pouredinto water and extracted with ethyl acetate (4×25 mL). The combinedorganic extracts were washed with brine, concentrated, and purified byreverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 15 minutes] to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 0.82-1.00 (m, 1H), 1.17-1.30 (m, 1H), 1.32-1.42 (m,1H), 1.55-1.64 (m, 1H), 1.78-1.99 (m, 3H), 2.15 (s, 3H), 2.40 (s, 6H),2.66 (dd, J=17, 7 Hz, 1H), 3.06-3.15 (m, 3H), 4.03 (t, J=3 Hz, 1H),4.30-4.37 (m, 2H), 6.95 (dd, J=8, 1 Hz, 1H), 7.08-7.14 (m, 2H), 7.26 (d,J=8 Hz, 1H), 7.32 (dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS(DCI/NH₃) m/z 360 (M+H)⁺.

Example 115(7R,11S)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

Purification of the racemic mixture from Example 114B (60 mg) bypreparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5μm column, 21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing0.1% diethylamine, flow rate 40 mL/minute) afforded the title compoundas the first-eluting enantiomer: ¹H NMR (300 MHz, CDCl₃) δ ppm 0.82-1.01(m, 1H), 1.16-1.28 (m, 1H), 1.31-1.41 (m, 1H), 1.54-1.65 (m, 1H),1.77-1.98 (m, 3H), 2.15 (s, 3H), 2.40 (s, 6H), 2.65 (dd, J=17, 7 Hz,1H), 3.06-3.15 (m, 3H), 4.03 (t, J=3 Hz, 1H), 4.30-4.37 (m, 2H), 6.95(dd, J=8, 1 Hz, 1H), 7.08-7.15 (m, 2 H), 7.26 (d, J=8 Hz, 1H), 7.33 (dd,J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 360 (M+H)⁺.

Example 116(7S,11R)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

Purification of the racemic mixture from Example 114B (60 mg) bypreparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5μm column, 21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing0.1% diethylamine, flow rate 40 mL/minute) afforded the title compoundas the second-eluting enantiomer: ¹H NMR (300 MHz, CDCl₃) δ ppm0.82-1.00 (m, 1H), 1.17-1.28 (m, 1H), 1.32-1.41 (m, 1H), 1.55-1.65 (m,1H), 1.77-1.99 (m, 3H), 2.15 (s, 3H), 2.40 (s, 6H), 2.65 (dd, J=17, 7Hz, 1H), 3.05-3.15 (m, 3H), 4.03 (t, J=3 Hz, 1H), 4.30-4.37 (m, 2H),6.95 (dd, J=8, 1 Hz, 1H), 7.09-7.14 (m, 2H), 7.26 (d, J=8 Hz, 1H), 7.33(dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 360 (M+H)⁺.

Example 1175-[2-(6-chloropyridin-3-yl)ethyl]-2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indoleExample 117A 2-(6-chloropyridin-3-yl)-N-p-tolylacetamide

In a 500 mL round-bottom flask were combined2-(6-chloropyridin-3-yl)acetic acid (10.3 g, 60.0 mmol; Oakwood),p-toluidine (6.43 g, 60.0 mmol; Aldrich) and N,N-diisopropylethylamine(34.3 mL, 198 mmol; Aldrich) in tetrahydrofuran (220 mL). The mixturewas stirred at room temperature for 1 hour, and thenO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU; 25.1 g, 66.0 mmol; Aldrich) was added. After16 hours, the reaction was concentrated, the residue dissolved in ethylacetate (500 mL) and washed with water (50 mL). The organic phase wasconcentrated and purified by flash chromatography (silica gel,hexanes/ethyl acetate, 2:1) to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 2.28 (s, 3H), 3.71 (s, 2H), 7.11 (d, J=8 Hz,2H), 7.37-7.46 (m, 3H), 7.81 (dd, J=8, 3 Hz, 1H), 8.33 (d, J=2 Hz, 1H);MS (DCI/NH₃) m/z 261 (M+H)⁺.

Example 117B N-(2-(6-chloropyridin-3-yl)ethyl)-4-methylaniline

A 500 mL reaction flask containing2-(6-chloropyridin-3-yl)-N-p-tolylacetamide (12 g, 46 mmol; Example117A) in tetrahydrofuran (200 mL) was treated with 1 Mborane-tetrahydrofuran (100 mL, 100 mmol; Aldrich) and then heated toreflux with stirring for 16 hours. After cooling the reaction mixture toroom temperature, it was quenched with ethanol, concentrated andpurified by flash chromatography (silica gel, hexanes/ethyl acetate,2:1) to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm2.19 (s, 3H), 2.89 (t, J=7 Hz, 2H), 3.35 (t, J=7 Hz, 2H), 6.56 (d, J=8Hz, 2H), 6.93 (d, J=8 Hz, 2H), 7.37 (d, J=8 Hz, 1H), 7.70 (dd, J=8, 2Hz, 1H), 8.21 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 247 (M+H)⁺.

Example 117C N-(2-(6-chloropyridin-3-yl)ethyl)-N-p-tolylnitrous amide

A 250 mL reaction flask was charged withN-(2-(6-chloropyridin-3-yl)ethyl)-4-methylaniline (5 g, 20.3 mmol;Example 117B) in 1 N aqueous HCl (22 mL) and ethanol (20 mL). Themixture was stirred at room temperature until complete dissolution wasobtained (˜2 hours). The reaction then was cooled in an ice bath and asolution of sodium nitrite (1.55 g, 22.47 mmol; Aldrich) in water (10mL) was added dropwise with stirring. After the addition was complete,the reaction mixture was allowed to warm briefly to room temperature,then it was cooled again in an ice bath before filtering. The filtercake was washed with water several times and then dried to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 2.38 (s, 3H), 2.88(t, J=7 Hz, 1H), 4.34 (t, J=7 Hz 2H), 7.25-7.39 (m, 5H), 7.63 (dd, J=8,2 Hz, 1H), 8.11 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 276 (M+H)⁺.

Example 117D 2-chloro-5-(2-(1-p-tolylhydrazinyl)ethyl)pyridine

A 250 mL flask was charged withN-(2-(6-chloropyridin-3-yl)ethyl)-N-p-tolylnitrous amide (5.2 g, 18.9mmol; Example 117C) and ammonium carbonate (3.62 g, 37.7 mmol; Aldrich)in acetonitrile (10 mL) and water (30 mL). The mixture was cooled in anice bath and zinc dust (1.63 g, 24.5 mmol; Aldrich) was added veryslowly over 2 hours. After stirring for an additional 1 hour, thereaction was filtered to remove the solid material. The filtrate wasconcentrated and extracted with ethyl acetate. The organic extracts werethen purified by flash chromatography (silica gel, hexane/ethyl acetate,2:1) to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm2.22 (s, 3H), 2.89-2.99 (m, 2H), 3.52-3.60 (m, 2H), 6.81-6.90 (m, 2H),6.98-7.04 (m, 2H), 7.36 (d, J=8 Hz, 1H), 7.74 (dd, J=8, 3 Hz, 1H), 8.25(d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 262 (M+H)⁺.

Example 117E2,12-Dimethyl-5-[2-(6-chloropyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

In a 25 mL round-bottomed flask were combined2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (50 mg, 0.19 mmol;Example 117D), pseudopelletierine hydrochloride (40 g, 0.21 mmol;Acros), and concentrated sulfuric acid (31 μL) in dioxane (8 mL). Thereaction mixture was heated to 80° C. for 6 hours, then cooled to roomtemperature. The solvent was removed under vacuum and residue waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile inbuffer (0.1% trifluoroacetic acid) over 15 minutes] to afford the titlecompound as the bistrifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 0.94-1.13 (m, 1H), 1.39-1.51 (m, 1H), 1.71-1.80 (m,1H), 1.91-2.17 (m, 3H), 2.43 (s, 3H), 2.50 (d, J=18 Hz, 1H), 2.66 (s,3H), 2.96 (dd, J=18, 7 Hz, 1H), 3.14-3.23 (m, 2H), 3.83 (t, J=5 Hz, 1H),4.41 (t, J=6 Hz, 2H), 4.90 (d, J=2 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 7.24(s, 1H), 7.32 (d, J=8 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.50 (dd, J=8, 2Hz, 1H), 7.77 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 380 (M+H)⁺.

Example 118(7R,11S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-SH-7,11-epiminocycloocta[b]indoleExample 118A2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

In a 100 mL round-bottom flask were combined p-tolylhydrazinehydrochloride (1.80 g, 11.4 mmol; Alfa Aesar),9-azabicyclo[3.3.1]nonan-3-one hydrochloride (2.0 g, 11.4 mmol; AccelaChemBio), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). Thereaction mixture was heated to 80° C. for 2.5 hours, then cooled to roomtemperature. The solvent was decanted, and the residue was dissolved inwater (20 mL) and basified with solid potassium carbonate to pH ˜12.This solution was extracted with dichloromethane (3×50 mL), and thecombined organic phases were dried over magnesium sulfate. Afterremoving the solvent under vacuum, the residue was purified by silicagel chromatography (CH₂Cl₂/CH₃OH, 3:1) to afford the title compound: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.39-1.50 (m, 2H), 1.75 (d, J=14 Hz, 2H),1.91-2.07 (m, 2H), 2.38 (s, 3H), 2.72 (d, J=17 Hz, 1H), 3.27-3.39 (m,1H), 3.70 (t, J=5 Hz, 1H), 4.55 (t, J=3 Hz, 1H), 6.88 (dd, J=8, 1 Hz,1H), 7.14 (s, 1H), 7.18 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 227 (M+H)⁺.

Example 118B(7R,11S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (227mg, 1.0 mmol; Example 118A) and 5-ethynyl-2-methylpyridine (235 mg, 2.0mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to give both (E)- and (Z)-isomers. Individual enantiomers ofthe (Z)-isomer were obtained by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes) toafford the title compound as the first-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.33-1.48 (m, 2H), 1.49-1.58 (m, 1H), 1.68-1.78(m, 1H), 1.83-2.07 (m, 2H), 2.37 (s, 3H), 2.40 (s, 3H), 2.46 (d, J=18Hz, 1H), 3.06 (dd, J=17, 7 Hz, 1H), 3.54-3.61 (m, 1H), 4.48 (t, J=3 Hz,1H), 6.64 (d, J=8 Hz, 1H), 6.81-6.91 (m, 2H), 6.97 (d, J=8 Hz, 1H), 7.06(d, J=8 Hz, 1H), 7.18-7.25 (m, 2H), 8.00 (d, J=2 Hz, 1H); MS (DCI/NH₃)m/z 344 (M+H)⁺.

Example 119(7S,11R)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (227mg, 1.0 mmol; Example 118A) and 5-ethynyl-2-methylpyridine (235 mg, 2.0mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to give both (E)- and (Z)-isomers. Individual enantiomers ofthe (Z)-isomer were obtained by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes) toafford the title compound as the second-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.33-1.50 (m, 2H), 1.54 (dd, J=14, 2 Hz, 1H),1.74 (dd, J=13, 2 Hz, 1H), 1.85-2.07 (m, 2H), 2.37 (s, 3H), 2.40 (s,3H), 2.47 (d, J=18 Hz, 1H), 3.07 (dd, J=18, 7 Hz, 1H), 3.59 (t, J=5 Hz,1H), 4.50 (t, J=3 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.81-6.92 (m, 2H), 6.97(d, J=8 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 7.16-7.26 (m, 2H), 7.99 (d, J=2Hz, 1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 120(7R,11S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

A suspension of2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(750 mg, 2.18 mmol; from Example 118B) and platinum(IV) oxide (105 mg,0.462 mmol; Aldrich) in 2-propanol (30 mL) was heated to 65° C. underhydrogen balloon atmosphere (1 atm) for 16 hours, then cooled to roomtemperature. The catalyst and solvent were removed, and the residue waspurified by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient ofCH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40 mL/minute, 20minutes) to afford the title compound as the first-eluting enantiomer:¹H NMR (300 MHz, CDCl₃) δ ppm 0.96-1.14 (m, J=18, 18, 9, 5 Hz, 1H),1.25-1.40 (m, 2H), 1.60 (dd, J=13, 2 Hz, 1H), 1.75-1.96 (m, 2H), 2.03(d, J=17 Hz, 1H), 2.39 (s, 3H), 2.42 (s, 3H), 2.87 (dd, J=17, 7 Hz, 1H),3.00-3.21 (m, 2H), 3.43 (t, J=6 Hz, 1H), 4.20-4.42 (m, 3H), 6.92 (dd,J=8, 1 Hz, 1H), 7.09-7.15 (m, 2H), 7.20 (d, J=8 Hz, 1H), 7.36 (dd, J=8,2 Hz, 1H), 7.88 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 346 (M+H)⁺.

Example 121(7S,11R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

Purification of the racemic mixture from Example 120 by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine, flow rate 40 mL/minute, 20 minutes) afforded the titlecompound as the second-eluting enantiomer: ¹H NMR (300 MHz, CDCl₃) δ ppm0.96-1.15 (m, J=18, 18, 9, 4 Hz, 1H), 1.25-1.40 (m, 2H), 1.61 (dd, J=13,2 Hz, 1H), 1.75-1.95 (m, 2H), 2.03 (d, J=17 Hz, 1H), 2.39 (s, 3H), 2.42(s, 3H), 2.87 (dd, J=17, 8 Hz, 1H), 2.99-3.21 (m, 2H), 3.44 (t, J=5 Hz,1H), 4.20-4.42 (m, 3H), 6.92 (dd, J=8, 1 Hz, 1H), 7.08-7.15 (m, 2H),7.21 (d, J=8 Hz, 1H), 7.36 (dd, J=8, 2 Hz, 1H), 7.88 (d, J=2 Hz, 1H); MS(DCI/NH₃) m/z 346 (M+H)⁺.

Example 1222,12-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107mg, 0.915 mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to give the title compound as the minor of two alkeneisomers: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.30-1.53 (m, 2H),1.73-1.88 (m, 2H), 1.97-2.17 (m, 2H), 2.43 (s, 3H), 2.53 (s, 3H), 2.55(s, 3H), 2.88 (d, J=18 Hz, 1H), 3.40-3.51 (m, 1H), 3.56 (br. s, 1H),4.41 (s, 1H), 6.88 (d, J=15 Hz, 1H), 7.10 (dd, J=8, 1 Hz, 1H), 7.24 (s,1H), 7.30 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.74 (d, J=15 Hz, 1H),7.97 (dd, J=8, 2 Hz, 1H), 8.53 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 358(M+H)⁺.

Example 123(7R,11S)-2,12-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107mg, 0.915 mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to give the racemic mixture of the title compound as themajor of two alkene isomers. The individual enantiomers from the racemicmixture of the major alkene isomer were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to afford the title compound as the first-eluting enantiomer: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.18-1.30 (m, 1H), 1.30-1.41 (m, 1H), 1.48(dd, J=13, 2 Hz, 1H), 1.69 (dd, J=13, 2 Hz, 1H), 1.83-2.09 (m, 2H), 2.26(d, J=17 Hz, 1H), 2.28 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.89 (dd,J=18, 7 Hz, 1H), 3.17 (t, J=5 Hz, 1H), 4.13 (s, 1H), 6.64 (d, J=9 Hz,1H), 6.84-6.90 (m, 1H), 6.92-7.01 (m, 2H), 7.03-7.09 (m, 1H), 7.15-7.22(m, 2H), 7.96 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 358 (M+H)⁺.

Example 124(7S,11R)-2,12-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107mg, 0.915 mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to give the racemic mixture of the title compound as themajor of two alkene isomers. The individual enantiomers from thisracemic mixture were separated by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine) to afford the titlecompound as the second-eluting enantiomer: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.18-1.41 (m, 2H), 1.48 (dd, J=13, 2 Hz, 1H), 1.65-1.75 (m, 1H),1.83-2.08 (m, 2H), 2.26 (d, J=17 Hz, 1H), 2.28 (s, 3 H), 2.38 (s, 3H),2.39 (s, 3H), 2.90 (dd, J=18, 7 Hz, 1H), 3.17 (t, J=5 Hz, 1H), 4.13 (s,1H), 6.64 (d, J=8 Hz, 1H), 6.84-6.91 (m, 1H), 6.92-7.10 (m, 3H),7.15-7.23 (m, 2H), 7.96 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 358 (M+H)⁺.

Example 125(7R,11S)-2-methyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (227mg, 1.00 mmol; Example 118A) and 5-ethynyl-2-methylpyridine (235 mg, 2.0mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to produce both (E) and (Z) isomers of the title compound.Individual enantiomers of the (E) isomer were obtained by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine) to afford the title compound as the first-elutingenantiomer: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.35-1.54 (m, 2H),1.66-1.81 (m, 2H), 1.89-2.07 (m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.84(d, J=17 Hz, 1H), 3.33-3.45 (m, 1H), 3.69 (t, J=6 Hz, 1H), 4.43 (s, 1H),6.83 (d, J=15 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 7.22 (s, 1H), 7.29 (d, J=8Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.73 (d, J=15 Hz, 1H), 7.95 (dd, J=8, 2Hz, 1H), 8.51 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 126(7S,11R)-2-methyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (227mg, 1.00 mmol; Example 118A) and 5-ethynyl-2-methylpyridine (235 mg, 2.0mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to produce both (E)- and (Z)-isomers of the title compound.Individual enantiomers of the (E)-isomer were obtained by preparativechiral super critical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine) to afford the title compound as the second-elutingenantiomer: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.38-1.63 (m, 2H),1.83-1.96 (m, 2H), 1.98-2.18 (m, 2H), 2.44 (s, 3H), 2.54 (s, 3H), 3.10(d, J=18 Hz, 1H), 3.55 (dd, J=18, 7 Hz, 1H), 4.01 (t, J=5 Hz, 1H), 4.83(s, 1H), 6.89 (d, J=15 Hz, 1H), 7.13 (dd, J=8, 1 Hz, 1H), 7.31 (d, J=9Hz, 2H), 7.68 (d, J=8 Hz, 1H), 7.73 (d, J=15 Hz, 1H), 7.97 (dd, J=8, 2Hz, 1H), 8.54 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 127(7R,11S)-2-methyl-5-[2-(2-methylphenyl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110mg, 0.486 mmol; Example 118A) and 1-methyl-2-vinylbenzene (115 mg, 0.972mmol; Aldrich) was performed according to the procedure described inExample 114B to provide title compound as a racemic mixture. Individualenantiomers were obtained by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes) toafford the title compound as the first-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.13-1.33 (m, 3H), 1.60-1.96 (m, 4H), 2.00 (s,3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.98-3.08 (m, 1H), 3.16(ddd, J=14, 9, 6 Hz, 1H), 3.36-3.43 (m, 1H), 4.20 (ddd, J=15, 9, 5 Hz,1H), 4.32-4.42 (m, 2H), 6.90-6.98 (m, 2H), 6.99-7.11 (m, 3H), 7.14 (s,1H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 345 (M+H)⁺.

Example 128(7S,11R)-2-methyl-5-[2-(2-methylphenyl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110mg, 0.486 mmol; Example 118A) and 1-methyl-2-vinylbenzene (115 mg, 0.972mmol; Aldrich) was performed according to the procedure described inExample 114B to afford the title compound as a racemic mixture.Individual enantiomers were obtained by preparative chiral supercriticalfluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C.,10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes)to afford the title compound as the second-eluting enantiomer: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.10-1.34 (m, 3H), 1.59-1.96 (m, 4H), 2.00(s, 3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.97-3.09 (m, 1H),3.11-3.22 (m, 1H), 3.37-3.43 (m, 1H), 4.20 (ddd, J=14, 9, 5 Hz, 1H),4.31-4.42 (m, 2H), 6.90-6.97 (m, 2H), 6.99-7.11 (m, 3H), 7.14 (s, 1H),7.27 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 345 (M+H)⁺.

Example 129(7R,11S)-5-[2-(2,5-dimethylphenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110mg, 0.486 mmol; Example 118A) and 1,4-dimethyl-2-vinylbenzene (129 mg,0.972 mmol; Aldrich) was performed according to the procedure describedin Example 114B to afford the title compound as a racemic mixture.Individual enantiomers were obtained by preparative chiral supercriticalfluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C.,10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes)to afford the title compound as the first-eluting enantiomer: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.07-1.35 (m, 3H), 1.60-1.96 (m, 4H), 1.99(s, 3H), 2.15 (s, 3H), 2.41 (s, 3H), 2.82 (dd, J=17, 7 Hz, 1H),2.94-3.16 (m, 2H), 3.38-3.45 (m, 1H), 4.19 (ddd, J=15, 9, 5 Hz, 1H),4.30-4.41 (m, 2H), 6.69 (s, 1H), 6.84-6.99 (m, 3H), 7.14 (s, 1H), 7.27(d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 359 (M+H)⁺.

Example 130(7S,11R)-5-[2-(2,5-dimethylphenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110mg, 0.486 mmol; Example 118A) and 1,4-dimethyl-2-vinylbenzene (129 mg,0.972 mmol; Aldrich) was performed according to the procedure describedin Example 114B to afford the title compound as a racemic mixture.Individual enantiomers were obtained by preparative chiral supercriticalfluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C.,10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes)to afford the title compound as the second-eluting enantiomer: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.07-1.32 (m, 3H), 1.62 (dd, J=13, 2 Hz,1H), 1.70-1.95 (m, 3H), 2.00 (s, 3H), 2.15 (s, 3H), 2.40 (s, 3H), 2.79(dd, J=17, 7 Hz, 1H), 2.94-3.16 (m, 2H), 3.34-3.40 (m, 1H), 4.19 (ddd,J=14, 9, 5 Hz, 1H), 4.28-4.39 (m, 2H), 6.69 (s, 1H), 6.85-6.97 (m, 3H),7.13 (s, 1H), 7.26 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 359 (M+H)⁺.

Example 131(7R,11S)-5-[2-(4-chlorophenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (226mg, 1.0 mmol; Example 118A) and 1-chloro-4-vinylbenzene (277 mg, 1.99mmol; Aldrich) was performed according to the procedure described inExample 114B to afford the title compound as a racemic mixture.Individual enantiomers were obtained by preparative chiral supercriticalfluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C.,10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minutes)to afford the title compound as the first-eluting enantiomer: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.03-1.17 (m, 1H), 1.28-1.43 (m, 2H), 1.65(d, J=13 Hz, 1H), 1.76-1.94 (m, 2H), 1.98 (d, J=17 Hz, 1H), 2.40 (s,3H), 2.90 (dd, J=17, 8 Hz, 1H), 2.97-3.15 (m, 2H), 3.47-3.54 (m, 1H),4.15-4.27 (m, 1H), 4.31-4.44 (m, 2H), 6.93-6.99 (m, 2H), 7.15 (s, 1H),7.18 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 365 367(M+H)⁺.

Example 132(7S,11R)-5-[2-(4-chlorophenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (226mg, 1.0 mmol; Example 118A) and 1-chloro-4-vinylbenzene (277 mg, 1.99mmol; Aldrich) was performed according to the procedure described inExample 114B to afford the title compound as a racemic mixture.Individual enantiomers were obtained by preparative chiral supercriticalfluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C.,10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine, 20 minute) toafford the title compound as the second-eluting enantiomer: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.04-1.20 (m, 1H), 1.29-1.44 (m, 2H), 1.66 (dd,J=13, 2 Hz, 1H), 1.78-2.04 (m, 3H), 2.40 (s, 3H), 2.92 (dd, J=17, 7 Hz,1H), 2.98-3.17 (m, 2H), 3.50-3.57 (m, 1H), 4.21 (ddd, J=15, 9, 6 Hz,1H), 4.32-4.42 (m, 1H), 4.43-4.47 (m, 1H), 6.92-7.00 (m, 3H), 7.14-7.21(m, 3H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 365 367 (M+H)⁺.

Example 133(7R,11S)-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110mg, 0.486 mmol; Example 118A) and 1-(trifluoromethyl)-3-vinylbenzene(167 mg, 1.00 mmol; Aldrich) was performed according to the proceduredescribed in Example 114B to afford the title compound as a racemicmixture. Individual enantiomers were obtained by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1% diethylamine,20 minutes) to afford the title compound as the first-elutingenantiomer: ¹H NMR (300 MHz, methanol-d₄) δ ppm 0.97-1.14 (m, 1H),1.23-1.43 (m, 2H), 1.62 (dd, J=13, 2 Hz, 1H), 1.75-1.97 (m, 2H), 2.09(d, J=17 Hz, 1H), 2.40 (s, 3H), 2.90 (dd, J=17, 7 Hz, 1H), 3.10-3.25 (m,2H), 3.49 (t, J=5 Hz, 1H), 4.27-4.42 (m, 3H), 6.93 (dd, J=8, 1 Hz, 1H),7.14 (s, 1H), 7.18-7.24 (m, 2H), 7.29 (s, 1H), 7.35 (t, J=8 Hz, 1H),7.42-7.48 (m, 1H); MS (DCI/NH₃) m/z 399 (M+H)⁺.

Example 1342-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (1132mg, 5.0 mmol; Example 118A) and 1-ethynyl-3-(trifluoromethyl)benzene(1701 mg, 10.0 mmol; Aldrich) was performed according to the proceduredescribed in Example 20 to afford the title compound as the majorisomeric product: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.34-1.54 (m, 2H),1.67-1.80 (m, 2H), 1.89-2.07 (m, 2H), 2.42 (s, 3H), 2.84 (d, J=17 Hz,1H), 3.34-3.45 (m, 1H), 3.68 (t, J=5 Hz, 1H), 4.41 (t, J=3 Hz, 1H), 6.91(d, J=15 Hz, 1H), 7.06 (dd, J=8, 1 Hz, 1H), 7.22 (s, 1H), 7.46-7.57 (m,2H), 7.65 (d, J=8 Hz, 1H), 7.72-7.84 (m, 3H); MS (DCI/NH₃) m/z 397(M+H)⁺.

Example 135(7S,11R)-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

In a 100 mL round-bottomed flask were combined2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(300 mg, 0.757 mmol; Example 134), 10% palladium on carbon (35 mg;Aldrich) in ethanol (30 mL). The reaction mixture was heated to 40° C.under a hydrogen balloon atmosphere for 16 hours, then cooled to roomtemperature. The catalyst and solvent were removed, and the residue waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile inbuffer (0.1% trifluoroacetic acid) over 15 minutes] to afford the titlecompound as a racemic mixture. This material was purified further bypreparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5μm column, 21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing0.1% diethylamine, 20 minutes) to afford the title compound: ¹H NMR (300MHz, CDCl₃) δ ppm 0.97-1.17 (m, 1H), 1.22-1.42 (m, 2H), 1.61 (dd, J=13,2 Hz, 1H), 1.74-1.95 (m, 2H), 2.06 (d, J=17 Hz, 1H), 2.40 (s, 3H), 2.87(dd, J=17, 7 Hz, 1H), 3.10-3.23 (m, 2H), 3.44 (t, J=6 Hz, 1H), 4.25-4.44(m, 3H), 6.93 (d, J=8 Hz, 1H), 7.13 (s, 1H), 7.17-7.23 (m, 2H), 7.29 (s,1H), 7.35 (t, J=8 Hz, 1H), 7.42-7.48 (m, 1H); MS (DCI/NH₃) m/z 399(M+H)⁺.

Example 13612-ethyl-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

In a 100 mL round-bottom flask were combined2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(300 mg, 0.757 mmol; Example 134) and 10% palladium on carbon (35 mg;Aldrich) in ethanol (30 mL). The reaction mixture was heated to 40° C.under a hydrogen balloon atmosphere for 16 hours, then cooled to roomtemperature. The catalyst and solvent were removed, and the residue waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile inbuffer (0.1% trifluoroacetic acid) over 15 minutes] to afford the titlecompound as a byproduct as the trifluoroacetic acid salt: ¹H NMR (300MHz, CDCl₃) δ ppm 0.90-1.08 (m, 4H), 1.18-1.30 (m, 1H), 1.39 (ddd, J=13,4, 2 Hz, 1H), 1.59 (dd, J=13, 2 Hz, 1H), 1.77-1.99 (m, 3H), 2.18-2.33(m, 2H), 2.40 (s, 3H), 2.55 (dd, J=17, 7 Hz, 1H), 3.14-3.26 (m, 3H),4.16 (t, J=3 Hz, 1H), 4.27-4.45 (m, 2H), 6.94 (dd, J=8, 1 Hz, 1H),7.08-7.16 (m, 2H), 7.23-7.28 (m, 2H), 7.31 (t, J=8 Hz, 1H), 7.40-7.45(m, 1H); MS (DCI/NH₃) m/z 427 (M+H)⁺.

Example 137(7R,11S)-2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

Purification of the racemic mixture from Example 134 by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine, flow rate 40 mL/minute, 20 minutes) afforded the titlecompound as the first-eluting enantiomer: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.37-1.56 (m, 2H), 1.70-1.83 (m, 2H), 1.90-2.09 (m, 2H), 2.42 (s,3H), 2.89 (d, J=17 Hz, 1H), 3.41 (dd, J=18, 7 Hz, 1H), 3.73 (t, J=5 Hz,1H), 4.49 (t, J=3 Hz, 1H), 6.92 (d, J=15 Hz, 1H), 7.07 (dd, J=8, 1 Hz,1H), 7.23 (s, 1H), 7.47-7.58 (m, 2H), 7.66 (d, J=8 Hz, 1H), 7.76 (d,J=15 Hz, 1H), 7.79-7.84 (m, 2H); MS (DCI/NH₃) m/z 397 (M+H)⁺.

Example 138(7S,11R)-2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

Purification of the racemic mixture from Example 134 by preparativechiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column,21×250 mm, 35° C., 10-50% gradient of CH₃OH—CO₂ containing 0.1%diethylamine, flow rate 40 mL/minute, 20 minutes) afforded the titlecompound as the second-eluting enantiomer: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.38-1.56 (m, 2H), 1.72-1.83 (m, 2H), 1.91-2.09 (m, 2H), 2.43 (s,3H), 2.90 (d, J=17 Hz, 1H), 3.42 (dd, J=17, 7 Hz, 1H), 3.75 (t, J=5 Hz,1H), 4.51 (s, 1H), 6.92 (d, J=15 Hz, 1H), 7.08 (dd, J=8, 1 Hz, 1H), 7.23(s, 1H), 7.48-7.58 (m, 2H), 7.66 (d, J=8 Hz, 1H), 7.76 (d, J=15 Hz, 1H),7.79-7.85 (m, 2H); MS (DCI/NH₃) m/z 397 (M+H)⁺.

Example 1392-methyl-5-{(Z)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (1132mg, 5.0 mmol; Example 118A) and 1-ethynyl-3-(trifluoromethyl)benzene(1701 mg, 10.0 mmol; Aldrich) was performed according to the proceduredescribed in Example 20 to afford the title compound as the minorisomeric product: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.26-1.44 (m,J=27, 14, 4, 4 Hz, 1H), 1.46-1.58 (m, 1H), 1.67 (dd, J=15, 2 Hz, 1H),1.86-2.18 (m, 3H), 2.40 (s, 3H), 2.68 (d, J=18 Hz, 1H), 3.24-3.31 (m,1H), 4.01 (t, J=6 Hz, 1H), 5.04 (t, J=3 Hz, 1H), 6.84 (d, J=9 Hz, 1H),6.92-7.03 (m, 3H), 7.18-7.24 (m, 2H), 7.29-7.39 (m, 2H), 7.44-7.50 (m,1H); MS (DCI/NH₃) m/z 397 (M+H)⁺.

Example 1405-[2-(6-methylpyridin-3-yl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indoleExample 140A2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

In a 30 mL microwave reaction tube were combined4-(trifluoromethoxy)phenylhydrazine hydrochloride (1062 mg, 5.0 mmol;Maybridge), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (878 mg, 5.0mmol; Accela ChemBio), and 1 N HCl in acetic acid (15 mL, 15 mmol;Aldrich). The reaction mixture was microwaved at 150° C. (BiotagePersonal Chemistry, maximum 300 W) for 15 minutes, then cooled to roomtemperature. The solvent was removed, and the residue was dissolved inwater (20 mL) and basified with solid potassium carbonate to ˜pH 12.This solution was extracted with dichloromethane (3×50 mL), and thecombined organic phases were dried over magnesium sulfate. Afterremoving the solvent under vacuum, the residue was purified by flashchromatography (silica gel, CH₂Cl₂/CH₃OH, 3:1) to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.33-1.52 (m, 2H), 1.64-1.78 (m,2H), 1.89-2.06 (m, 2H), 2.68 (d, J=17 Hz, 1H), 3.25-3.34 (m, 1H), 3.62(t, J=5 Hz, 1H), 4.43 (t, J=3 Hz, 1H), 6.93 (ddd, J=9, 2, 1 Hz, 1H),7.22 (d, J=1 Hz, 1H), 7.31 (d, J=9 Hz, 1H); MS (DCI/NH₃) m/z 297 (M+H)⁺.

Example 140B5-[2-(6-methylpyridin-3-yl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(148 mg, 0.500 mmol; Example 140A) and 2-methyl-5-vinylpyridine (119 mg,1.00 mmol; IBScreen) was performed according to the procedure describedin Example 114B to afford the title compound: ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.09-1.22 (m, 1H), 1.29-1.39 (m, J=7, 7 Hz, 1H), 1.46(d, J=14 Hz, 1H), 1.75 (d, J=14 Hz, 1H), 2.26-2.44 (m, 3H), 2.48 (s,3H), 2.95-3.04 (m, 1H), 3.05-3.13 (m, 1H), 3.47 (dd, J=18, 7 Hz, 1H),4.22-4.31 (m, 1H), 4.34-4.43 (m, 2H), 5.29 (s, 1H), 6.99 (d, J=8 Hz,1H), 7.23-7.31 (m, 2H), 7.51 (d, J=9 Hz, 1H), 7.60 (s, 1H), 8.37 (d, J=2Hz, 1H); MS (DCI/NH₃) m/z 416 (M+H)⁺.

Example 1415-[2-(2-methylphenyl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole

The coupling of2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole(148 mg, 0.500 mmol; Example 140A) and 1-methyl-2-vinylbenzene (118 mg,1.00 mmol; Aldrich) was performed according to the procedure describedin Example 114B to afford the title compound: ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.09-1.21 (m, 1H), 1.29-1.43 (m, 2H), 1.80 (d, J=13Hz, 1H), 2.02-2.10 (m, 4H), 2.27 (tt, J=14, 5 Hz, 1H), 2.41 (tt, J=14, 4Hz, 1H), 3.00 (dt, J=14, 5 Hz, 1H), 3.05-3.14 (m, 1H), 3.35 (dd, J=18, 7Hz, 1H), 4.21 (ddd, J=15, 9, 6 Hz, 1H), 4.28-4.33 (m, 1H), 4.37 (ddd,J=15, 5, 5 Hz, 1H), 5.29 (s, 1H), 6.92 (d, J=7 Hz, 1H), 7.06 (t, J=7 Hz,1H), 7.09-7.12 (m, 1H), 7.15 (t, J=7 Hz, 1H), 7.30 (d, J=10 Hz, 1H),7.54 (d, J=9 Hz, 1H), 7.63 (s, 1H); MS (DCI/NH₃) m/z 415 (M+H)⁺.

Example 1426-[2-(6-chloropyridin-3-yl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

In a 50 mL round-bottom flask were combined2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (0.272 g, 1.039 mmol;Example 117D), and 1-azabicyclo[3.2.2]nonan-4-one (0.188 g, 1.351 mmol;Example 2A) in dioxane (5 mL). After 10 minutes of warming to 50° C.,the suspension cleared. Concentrated sulfuric acid (0.277 mL, 5.20 mmol)was added and the mixture was heated at 80° C. After 1.5 hours, themixture was cooled and concentrated to about 3 mL. The residue wasdissolved in water (75 mL), basified with concentrated sodium hydroxide(30 mmol), extracted with chloroform (4×25 mL), dried over magnesiumsulfate, and concentrated. The residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15minutes] to give the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.63 (dddd, J=14.3, 9.3, 5.2, 2.4 Hz, 2H), 1.95 (ddt, J=13.6, 9.2, 5.2Hz, 2H), 2.39 (s, 3H), 2.95 (m, 1H), 3.00 (m, 2H), 3.06 (t, J=6.4 Hz,2H), 3.19 (ddd, J=14.1, 9.0, 5.2 Hz, 2H), 4.22 (s, 2H), 4.38 (t, J=6.4Hz, 2H), 6.92 (dd, J=8.5, 1.4 Hz, 1H), 7.11 (br s, 1H), 7.12 (d, J=8.5Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.36 (dd, J=8.3, 2.4 Hz, 1H), 7.79 (d,J=2.0 Hz, 1H); MS (DCI/NH₃) m/z 366 (M+H)⁺.

Example 1439-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 143A 2-trifluoromethyl-5-ethenylpyridine

Potassium vinyltrifluoroborate (362 mg, 2.7 mmol; Aldrich),5-bromo-2-trifluoromethylpyridine (539 mg, 2.38 mmol; Aldrich) andtriphenylphosphine (37.7 mg, 0.144 mmol) were added at room temperatureto a solution of cesium carbonate (2.16 g, 6.63 mmol) in water (2 mL).Tetrahydrofuran (18 mL) was added, and the reaction flask was evacuatedand purged with nitrogen (3 cycles). Palladium(II) chloride (9.2 mg,0.052 mmol) was added, and the reaction flask was again evacuated andpurged with nitrogen (3 cycles), then heated under nitrogen at 75-80° C.for 22 hours. The mixture was cooled to room temperature and the aqueouslayer was separated and extracted with ethyl ether (2×5 mL). Thecombined organic phase was concentrated by distillation through aVigreaux column at atmospheric pressure to a volume of approximately 2mL, and the residue was purified by flash chromatography (40 g silica,eluted with hexanes-ethyl acetate, 100:0-90:10). The product-containingfractions were combined and concentrated by distillation through aVigreaux column at atmospheric pressure to a volume of approximately 2mL, then distilled bulb-to-bulb (air bath 80-90° C./10-20 torr) toprovide the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 5.56 (d,J=10.9 Hz, 1H), 6.08 (d, J=17.6 Hz, 1H), 6.86 (dd, J=17.8, 11.0 Hz, 1H),7.77 (d, J=8.1 Hz, 1H), 8.11 (dd, J=8.3, 2.2 Hz, 1H), 8.74 (d, J=1.7 Hz,1H).

Example 143B9-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Sodium dispersion in paraffin (30%, 46 mg, 0.60 mmol; Aldrich) wascombined with9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (100 mg,0.442 mmol; Example 2B) in a 20 mL vial with stir bar and septum cap.Dimethyl sulfoxide (2.5 mL) was added, and the vial was evacuated andpurged with nitrogen (10 cycles). The mixture was stirred at roomtemperature for 10 minutes, and a solution of the product of Example143A (115 mg, 0.663 mmol) and hydroquinone (12 mg, 0.110 mmol) indimethyl sulfoxide (0.5 mL) was added. The vial was evacuated and purgedwith nitrogen (5 cycles) and the mixture was stirred with heating at115° C. for 39 hours. The dark brown mixture was cooled to roomtemperature, applied directly to a column of silica gel and eluted withchloroform, followed by CHCl₃—CH₃OH-14.8 M aqueous NH₄OH (90:10:1). Theproduct-containing fractions were combined and concentrated undervacuum, and the residue was purified by HPLC [Waters XBridge™ C18 5 μmOBD column, 30×100 mm, flow rate 40 mL/minute, 20-90% gradient ofacetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted topH 10 with ammonium hydroxide) over 20 minutes] to provide the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.46-1.64 (m, 2H),1.79-1.98 (m, 2H), 2.38 (s, 3H), 2.84-3.01 (m, 3H), 3.05-3.22 (m, 4H),4.16 (s, 2H), 4.42 (t, J=6.27 Hz, 2H), 6.89 (dd, J=8.48, 1.02 Hz, 1H),7.09 (d, J=7.80 Hz, 1H), 7.10 (d, J=0.68 Hz, 1H), 7.54 (dd, J=8.10, 1.70Hz, 1H), 7.59 (d, J=8.10 Hz, 1H), 8.12 (s, 1H); MS (ESI) m/z 400 (MH)⁺.

Example 1449-methyl-6-[(E)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indolebistrifluoroacetate

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (113 mg,0.50 mmol; Example 2B) and 3-ethynylpyridine (0.206 g, 2.0 mmol;Aldrich) was performed according to the procedure described in Example20 to afford a mixture of two isomers. Fractions containing the E-isomerwere repurified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient ofacetonitrile in 0.1% trifluoroacetic acid over 15 minutes) to afford thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 2.25-2.50 (m, 4H), 2.45 (s, 3H), 3.49-3.62 (m, 2H),3.64-3.82 (m, 3H), 4.78 (s, 2H), 7.00 (d, J=15 Hz, 1H), 7.17 (d, J=8 Hz,1H), 7.28 (s, 1H), 7.69-7.80 (m, 2H), 7.98 (d, J=15 Hz, 1H), 8.50 (d,J=8 Hz, 1H), 8.56 (d, J=5 Hz, 1H), 8.90 (s, 1H); MS (DCI/NH₃) m/z 330(M+H)⁺.

Example 1459-methyl-6-[(Z)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (113 mg,0.50 mmol; Example 2B) and 3-ethynylpyridine (0.206 g, 2.0 mmol;Aldrich) was performed according to the procedure described in Example20 to afford the title compound as one of two isomers: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.62-1.76 (m, 2H), 1.81-1.96 (m, 2H), 2.38 (s, 3H),2.92-3.08 (m, 3H), 3.09-3.22 (m, 2H), 4.21 (s, 2H), 6.75 (d, J=8 Hz,1H), 6.84-7.03 (m, 3H), 7.14-7.30 (m, 3H), 8.02 (d, J=2 Hz, 1H), 8.26(dd, J=5, 2 Hz, 1H); MS (DCI/NH₃) m/z 330 (M+H)⁺.

Example 1469-methyl-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (453 mg,2.0 mmol; Example 2B) and 5-ethynyl-2-methylpyridine (937 mg, 8.0 mmol;prepared as described in International Publication No. WO2005090333) wasperformed according to the procedure described in Example 20 to affordthe title compound as the minor isomer: ¹H NMR (300 MHz, methanol-d₄) δppm 2.05-2.19 (m, 4H), 2.41 (s, 3H), 2.53 (s, 3H), 3.00-3.14 (m, 2H),3.17-3.28 (m, 2H), 3.39-3.47 (m, 1H), 4.22 (s, 2H), 6.74 (d, J=15 Hz,1H), 7.03 (dd, J=8, 2 Hz, 1H), 7.12-7.19 (m, 1H), 7.29 (d, J=8 Hz, 1H),7.54 (d, J=8 Hz, 1H), 7.69 (d, J=14 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H),8.51 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 1479-methyl-6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (453 mg,2.0 mmol; Example 2B) and 5-ethynyl-2-methylpyridine (937 mg, 8.0 mmol;prepared as described in International Publication No. WO2005090333) wasperformed according to the procedure described in Example 20 to affordthe title compound as the major isomeric product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.65-1.79 (m, 2H), 1.83-1.97 (m, 2H), 2.38 (s, 3H),2.39 (s, 3H), 2.94-3.08 (m, 3H), 3.10-3.23 (m, 2H), 4.23 (s, 2H), 6.72(d, J=8 Hz, 1H), 6.84-6.98 (m, 3H), 7.03-7.18 (m, 3H), 7.88 (d, J=2 Hz,1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 1489-methyl-6-[2-(6-methylpyridazin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 148A 3-bromo-6-methylpyridazine

6-Methylpyridazin-3(2H)-one (2.5 g, 22.70 mmol, Alfa) and phosphorusoxybromide (16.27 g, 56.8 mmol, Aldrich) were heated at 90° C. under anitrogen atmosphere for 1.5 hours. After cooling, the mixture was pouredonto ice (100 g), neutralized with sodium bicarbonate, and the aqueousphase was extracted with CH₂Cl₂ (3×30 mL). The combined organic phasewas washed with 5% NaHCO₃, brine, dried (Na₂SO₄) and concentrated. Theresidue was dissolved in hot ethyl acetate and washed through a plug ofsilica gel, eluting with ethyl acetate and concentrated. MS (DCI/NH₃)m/z 172 (M+H)⁺, 190 (M+NH₄)⁺.

Example 148B 3-methyl-6-vinylpyridazine

Potassium vinyltrifluoroborate (1.71 g, 12.7 mmol, Aldrich),3-bromo-6-methylpyridazine (1.95 g, 11.3 mmol, Example 148A) andtriphenylphosphine (0.18 g, 0.67 mmol) were added at room temperature toa solution of Cs₂CO₃ (10.1 g, 31.0 mmol) in water (9.5 mL).Tetrahydrofuran (85 mL) was added, and the reaction flask was evacuatedand purged with nitrogen (3 cycles). PdCl₂ (50 mg, 0.28 mmol, Arcos) wasadded, and the reaction flask was again evacuated and purged withnitrogen (3 cycles), then heated under nitrogen at 75-80° C. for 22hours. The mixture was cooled to room temperature and the aqueous layerwas separated and extracted with ethyl ether (3×50 mL). The combinedorganic phase was concentrated to a volume of approximately 5 mL, andthe residue was purified by flash chromatography (80 g silica, elutedwith hexanes-ethyl acetate, 100:0-90:10): ¹H NMR (300 MHz, methanol-d₄)δ ppm 2.71 (s, 3H) 5.63 (d, J=11.2 Hz, 1H) 6.18 (d, J=18.3 Hz, 1H) 7.04(dd, J=17.8, 11.0 Hz, 1H) 7.23-7.34 (m, J=8.8 Hz, 1H) 7.49 (d, J=8.8 Hz,1H).

Example 148C9-methyl-6-[2-(6-methylpyridazin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Under nitrogen,9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (260 mg,1.15 mmol, Example 2B), was coupled with 3-methyl-6-vinylpyridazine (280mg, 1.86 mmol, Example 148B) according to the procedure described inExample 1B to give the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm1.65-1.76 (m, 2H) 1.85-1.95 (m, 2H) 2.43 (s, 3H) 2.67 (s, 3H) 2.96-3.09(m, 3H) 3.17-3.25 (m, 2H) 3.30 (t, J=7.1 Hz, 2H) 4.23 (s, 2H) 4.55 (t,J=7.1 Hz, 2H) 6.82 (d, J=8.5 Hz, 1H) 6.96 (dd, J=8.3, 1.2 Hz, 1H) 7.11(dd, J=17.1, 8.4 Hz, 2H) 7.16 (s, 1H); MS (DCI/NH₃) m/z 347 (M+H)⁺.

Example 1499-methyl-6-[2-(2-methylphenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (1.2 g,5.3 mmol; Example 2B) and in trifluoroacetic acid (20 mL) was cooled to−30° C. A solution of sodium cyanoborohydride (1.75 g, 26.5 mmol;Aldrich) in methanol (6.5 mL) was added dropwise over a period of 30minutes. The reaction mixture was allowed to slowly warm to ambienttemperature over a period of 30 minutes, then diluted with methanol(2×30 mL) and concentrated under vacuum. The residue was purified bypreparative HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flowrate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueousammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] toafford the indoline. A portion of this material (68 mg, 0.30 mmol),sodium (37 mg, 0.48 mmol; 30% dispersion in paraffin wax, Aldrich) and2-methyl-5-vinylpyridine (56 mg, 0.48 mmol; prepared as described inInternational Publication No. WO2001017968) were processed as describedin Example 106A and purified by preparative HPLC [Waters XBridge™ RP18column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid] to provide atrifluoroacetic acid salt. This was exposed in the air at ambienttemperature for 7 days and further purified by preparative HPLC [WatersXBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 35-99%gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide)] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.45-1.63 (m, 2H),1.71-1.90 (m, 2H), 2.02 (s, 3H), 2.39 (s, 3H), 2.79-2.95 (m, 3H),2.99-3.15 (m, 4H), 4.13 (s, 2H), 4.30 (t, J=6.6 Hz, 2H), 6.84-6.94 (m,2H), 6.97-7.06 (m, 3H), 7.07-7.11 (m, 1H), 7.14-7.19 (m, J=8.5 Hz, 1H);MS (APCI) m/z 345 (M+H)⁺.

Example 1506-[2-(2-fluorophenyl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (158 mg,0.70 mmol; Example 2B) and 1-fluoro-2-vinylbenzene (171 mg, 1.40 mmol;Aldrich) was performed according to the procedure described in Example114B to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.63-1.76 (m, 2H), 1.87-2.01 (m, 2H), 2.39 (s, 3H), 2.88-3.22 (m, 7H),4.16 (s, 2H), 4.33 (t, J=7 Hz, 2H), 6.86-7.26 (m, 7H); MS (DCI/NH₃) m/z349 (M+H)⁺.

Example 1516-[2-(4-chlorophenyl)ethyl]-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg,1.0 mmol; Example 2B) and 1-chloro-4-vinylbenzene (277 mg, 2.0 mmol;Aldrich) was performed according to the procedure described in Example114B to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.52-1.66 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (s, 3H), 2.85-3.03 (m, 5H),3.05-3.19 (m, 2H), 4.15 (s, 2H), 4.32 (t, J=7 Hz, 2H), 6.82-6.96 (m,3H), 7.06-7.22 (m, 4H); MS (DCI/NH₃) m/z 365 (M+H)⁺.

Example 1529-methyl-6-{2-[3-(trifluoromethyl)phenyl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg,1.0 mmol; Example 2B) and 1-(trifluoromethyl)-3-vinylbenzene (344 mg,2.0 mmol; Aldrich) was performed according to the procedure described inExample 114B to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.45-1.55 (m, 2H), 1.78-1.88 (m, 2H), 2.39 (s, 3H), 2.84-2.93 (m,3H), 3.04-3.13 (m, 4H), 4.13 (s, 2H), 4.37 (t, J=6 Hz, 2H), 6.91 (d, J=8Hz, 1H), 7.09 (s, 1H), 7.11-7.16 (m, 3H), 7.33 (t, J=8 Hz, 1H), 7.42 (d,J=8 Hz, 1H); MS (DCI/NH₃) m/z 399 (M+H)⁺.

Example 1539-methyl-6-[(Z)-2-(4-methylphenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (113 mg,0.50 mmol; Example 2B) and 1-ethynyl-4-methylbenzene (232 mg, 2.0 mmol;Aldrich) was performed according to the procedure described in Example20. The product was repurified by reverse-phase HPLC (Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradientof acetonitrile in 0.1% trifluoroacetic acid over 15 minutes) to affordthe title compound as a trifluoroacetate salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.66-1.80 (m, 2H), 1.98-2.12 (m, 2H), 2.22 (s, 3H),2.43 (s, 3H), 3.16-3.23 (m, 1H), 3.35-3.45 (m, 2H), 3.47-3.60 (m, 2H),4.73 (s, 2H), 6.72 (d, J=8 Hz, 2H), 6.76-6.84 (m, 2H), 6.97 (d, J=8 Hz,2H), 7.03 (d, J=9 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.25-7.27 (m, 1H); MS(DCI/NH₃) m/z 343 (M+H)⁺.

A-Example 154 ethyl(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetateExample 154A9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex

A suspension of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (903.4 mg,3.99 mmol; Example 2B) in tetrahydrofuran (20 mL) was treated with 1 MBH₃ in tetrahydrofuran (5 mL, 5 mmol; Aldrich), which was addedportionwise over 10 minutes. After 3 hours, the reaction mixture wasconcentrated in vacuo and purified by silica gel chromatography (elutingwith CH₂Cl₂) to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm2.06-2.22 (m, 4H), 2.43 (s, 3H), 3.00-3.04 (m, 1H), 3.23-3.33 (m, 2H),3.42-3.52 (m, 2H), 4.41 (s, 2H), 7.00 (dd, J=8.1, 1.7 Hz, 1H), 7.17 (d,J=1.6 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.72 (br s, 1H); MS (DCI/NH₃) m/z256 (M+NH₃—H)⁺.

Example 154B ethyl(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetateN-borane complex

A solution of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (357.4 mg, 1.49 mmol; Example 154A) in tetrahydrofuran (5 mL)was treated with potassium tert-butoxide (195.0 mg, 1.74 mmol; Aldrich)and the reaction was stirred at ambient temperature for 15 minutes.Ethyl bromoacetate (368.4 mg, 2.21 mmol; Aldrich) was then added andstirring was continued overnight (16 hours). The mixture was dilutedwith water (45 mL) and 1 M aqueous NaOH (5 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were dried overmagnesium sulfate, filtered and concentrated in vacuo. The resultingmaterial was purified by silica gel chromatography (eluting withdichloromethane). to afford the title compound: ¹H NMR (300 MHz, CDCl₃)δ ppm 1.25 (t, J=7.1 Hz, 3H) 2.06-2.20 (m, 4H), 2.43 (s, 3H), 3.04-3.07(m, 1H), 3.27-3.34 (m, 2H), 3.40-3.50 (m, 2H), 4.18 (q, J=7.1 Hz, 2H),4.42 (s, 2H), 7.46 (s, 2H), 7.25 (dd, J=8.5, 1.0 Hz, 1H), 7.11 (d, J=8.2Hz, 1H), 7.18-7.19 (m, 1H); MS (DCI/NH₃) m/z 342 (M+NH₃—H)⁺.

Example 154C ethyl(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetate

A solution of ethyl(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetateN-borane complex (100.7 mg, 0.31 mmol; Example 154B) in acetone (3 mL)was treated with 3 M aqueous hydrochloric acid (1 mL, 3 mmol) and thereaction was stirred at ambient temperature for 1 hour. The mixture wasconcentrated in vacuo, dissolved in methanol, stirred for 30 minutes,then concentrated again. The resulting material was triturated withmethanol/ether and isolated by filtration. The solid was washed withadditional ether to afford the title compound as the hydrochloride salt:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.26 (t, J=7.1 Hz, 3H) 2.30-2.37 (m,4H), 2.42 (s, 3H), 3.35-3.39 (m, 1H), 3.46-3.55 (m, 2H), 3.61-3.70 (m,2H), 4.20 (q, J=7.1 Hz, 2H), 4.73 (s, 2H), 5.03 (s, 2H), 7.02-7.05 (m,1H), 7.21-7.23 (m, 2H); MS (DCI/NH₃) m/z 313 (M+H)⁺. Anal. Calcd. forC₁₉H₂₄N₂O₂.HCl: C, 65.41; H, 7.22; N, 8.03; Cl, 10.16. Found: C, 65.17;H, 7.22; N, 8.03; Cl, 10.03.

Example 155N-(4-chlorophenyl)-2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetamideExample 155A(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)aceticacid N-borane complex

A suspension of ethyl(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetateN-borane complex (187.2 mg, 0.57 mmol; Example 154B) in ethanol (3 mL)and 1 M aqueous sodium hydroxide (3 mL) was heated to 60° C. for 1 hour.The reaction was diluted with water (30 mL), acidified with 1 M HCl (4mL), and extracted with dichloromethane (2×30 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm2.02-2.19 (m, 4H), 2.43 (s, 3H), 3.02-3.06 (m, 1H), 3.23-3.32 (m, 2H),3.40-3.49 (m, 2H), 4.42 (s, 2H), 4.82 (s, 2H), 7.03 (d, J=8.5 Hz, 1H),7.09 (d, J=8.1 Hz, 1H), 7.19 (s, 1H); MS (DCI/NH₃) m/z 314 (M+NH₃—H)⁺.

Example 155BN-(4-chlorophenyl)-2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetamideN-borane complex

A solution of(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)aceticacid N-borane complex (80.5 mg, 0.27 mmol; Example 155A) indichloromethane (3 mL) was treated with 4-chloroaniline (90.7 mg, 0.71mmol; Aldrich), 1-hydroxybenzotriazole hydrate (HOBt; 50.0 mg, 0.33mmol; Aldrich), 4-dimethylaminopyridine (DMAP; 12.2 mg, 0.10 mmol;Aldrich) and N-(3-dimethylaminopropyl-N′-ethylcarbodimide hydrochloride(EDCI; 81.2 mg, 0.42 mmol; Aldrich). After stirring for 6 hours, thereaction mixture was concentrated in vacuo and the residue was purifiedby preparative HPLC [Waters Nova-Pak® HR C18 6 μm 60 Å Prep-Pak®cartridge column (40×100 mm) using a gradient of 10-100% acetonitrile in10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70mL/minute] to provide the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 2.12-2.23 (m, 4H), 2.40 (s, 3H), 3.19-3.45 (m, 5H), 4.36 (s, 2H),4.96 (s, 2H), 6.98 (d, J=8.3 Hz, 1H), 7.14 (s, 1H), 7.20 (d, J=8.3 Hz,1H), 7.27-7.32 (m, 2H), 7.51-7.55 (m, 2H); MS (DCI/NH₃) m/z 423(M+NH₃—H)⁺.

Example 155CN-(4-chlorophenyl)-2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetamide

The product of Example 155B (48.4 mg, 0.12 mmol) was treated with 3 MHCl (aqueous) in acetone as described in Example 154C to afford thetitle compound as the hydrochloride salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 2.32-2.37 (m, 4H), 2.42 (s, 3H), 3.41-3.44 (m, 1H), 3.50-3.56 (m,2H), 3.60-3.70 (m, 2H), 4.74 (s, 2H), 5.05 (s, 2H), 7.05 (dd, J=8.5, 1.0Hz, 1H), 7.21-7.23 (m, 1H), 7.25-7.33 (m, 3H), 7.53-7.58 (m, 2H); MS(DCI/NH₃) m/z 394 (M+H)⁺. Anal. Calcd. for C₂₃H₂₄ClN₃O.HCl.0.1 H₂O: C,63.92; H, 5.88; N, 9.72. Found: C, 63.75; H, 5.65; N, 9.71.

Example 1562-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-N-[4-(trifluoromethoxy)phenyl]acetamideExample 156A2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-N-[4-(trifluoromethoxy)phenyl]acetamideN-borane complex

The coupling of(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)aceticacid N-borane complex (75.8 mg, 0.25 mmol; Example 155A) and4-trifluoromethoxyaniline (142.0 mg, 0.802 mmol, Aldrich) was performedas described in Example 155B to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 2.09-2.23 (m, 4H), 2.40 (s, 3H), 3.19-3.45 (m,5H), 4.36 (s, 2H), 4.98 (s, 2H), 6.96-7.00 (m, 1H), 7.14 (s, 1H),7.19-7.23 (m, 3H), 7.61-7.65 (m, 2H); MS (DCI/NH₃) m/z 473 (M+NH₃—H)⁺.

Example 156B2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-N-[4-(trifluoromethoxy)phenyl]acetamide

The product of Example 156A (44.2 mg, 0.10 mmol) was treated with 3 MHCl (aqueous) in acetone as described in Example 154C to afford thetitle compound as the hydrochloride salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 2.32-2.37 (m, 4H), 2.42 (s, 3H), 3.41-3.44 (m, 1H), 3.50-3.57 (m,2H), 3.60-3.67 (m, 2H), 4.74 (s, 2H), 5.06 (s, 2H), 7.05 (dd, J=8.5, 1.7Hz, 1H), 7.21-7.29 (m, 4H), 7.62-7.97 (m, 2H); MS (DCI/NH₃) m/z 444(M+H)⁺. Anal. Calcd. for C2₄H₂₄F₃N₃O₂.HCl.0.65 H₂O: C, 58.63; H, 5.39;N, 8.55. Found: C, 58.56; H, 5.24; N, 8.50.

Example 157(5aR*,10bS*)-9-methyl-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (1.2 g,5.3 mmol; Example 2B) in trifluoroacetic acid (20 mL) was cooled to −30°C. A solution of sodium cyanoborohydride (1.75 g, 26.5 mmol; Aldrich) inmethanol (6.5 mL) was added dropwise over a period of 30 minutes. Thereaction mixture was allowed to slowly warm to ambient temperature overa period of 30 minutes, then diluted with methanol (60 mL) andconcentrated under vacuum. The residue was purified by preparative HPLC[Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute,20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.54-1.75 (m, 1H),1.89-2.04 (m, 2H), 2.20 (s, 3H), 2.41-2.58 (m, 1H), 2.89-2.99 (m, 2H),2.99-3.13 (m, 2H), 3.21-3.41 (m, 3H), 3.54-3.63 (m, 1H), 4.12 (dd,J=8.7, 5.0 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.83(s, 1H); MS (+DCI) m/z 229 (M+H)⁺.

Example 158(5aR*,10bS*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole

9-Methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(210 mg, 0.61 mmol; Example 2) was processed as described in Example 157to provide the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.43-1.63 (m, 1H), 1.78-2.06 (m, 2H), 2.19 (s, 3H), 2.25-2.44 (m, 2H),2.48 (s, 3H), 2.67 (dd, J=13.9, 11.5 Hz, 1H), 2.73-2.91 (m, 4H),2.93-3.09 (m, 1H), 3.12-3.27 (m, 3H), 3.35-3.48 (m, 1H), 3.49-3.59 (m,1H), 3.85 (dd, J=8.7, 5.2 Hz, 1H), 6.41 (d, J=7.9 Hz, 1H), 6.79 (s, 1H),6.85 (d, J=8.3 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 7.64 (dd, J=7.9, 2.0 Hz,1H), 8.27 (d, J=2.0 Hz, 1H); MS (APCI) m/z 348 (M+H)⁺.

Example 159(5aS,10bR)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole

Individual enantiomers of the racemic mixture of Example 158 (150 mg,0.43 mmol) were separated by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40mL/minute) to afford the title compound as the first-eluting enantiomer:¹H NMR (500 MHz, methanol-d₄) δ ppm 1.46-1.56 (m, 1H), 1.81-1.90 (m,1H), 1.90-1.99 (m, 1H), 2.19 (s, 3H), 2.25-2.41 (m, 2H), 2.48 (s, 3H),2.62 (dd, J=14.0, 11.6 Hz, 1H), 2.71-2.87 (m, 4H), 2.90-3.04 (m, 1H),3.10-3.22 (m, 3H), 3.35-3.44 (m, 1H), 3.45-3.53 (m, 1H), 3.82 (dd,J=8.5, 5.2 Hz, 1H), 6.39 (d, J=7.9 Hz, 1H), 6.78 (s, 1H), 6.84 (d, J=7.6Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.62 (dd, J=7.9, 2.1 Hz, 1H), 8.26 (d,J=2.1 Hz, 1H); MS (APCI) m/z 348 (M+H)⁺.

Example 160(5aR,10bS)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole

Individual enantiomers of the racemic mixture of Example 158 (150 mg,0.43 mmol) were separated by preparative chiral supercritical fluidchromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50%gradient of CH₃OH—CO₂ containing 0.1% diethylamine, flow rate 40mL/minute) to afford the title compound as the second-elutingenantiomer: ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.43-1.58 (m, 1H),1.78-1.90 (m, 1H), 1.90-2.00 (m, 1H), 2.19 (s, 3H), 2.25-2.41 (m, 2H),2.48 (s, 3H), 2.63 (dd, J=14.0, 11.6 Hz, 1H), 2.72-2.87 (m, 4H),2.89-3.04 (m, 1H), 3.11-3.22 (m, 3H), 3.36-3.44 (m, 1H), 3.45-3.53 (m,1H), 3.83 (dd, J=8.5, 5.2 Hz, 1H), 6.40 (d, J=7.9 Hz, 1H), 6.78 (s, 1H),6.84 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.63 (dd, J=8.1, 2.3 Hz,1H), 8.26 (s, 1H); MS (APCI) m/z 348 (M+H)⁺.

Example 1619-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A mixture of (4-fluorophenyl)hydrazine hydrochloride (10.67 g, 65.6mmol; Aldrich) and 1-azabicyclo[3.2.2]nonan-4-one (9.13 g, 65.6 mmol;Example 2A) in 100 mL of 7% sulfuric acid in dioxane was heated to 100°C. for 30 hours. The reaction mixture was basified (˜pH 11) by theaddition of 50% aqueous sodium hydroxide then stirred in an ice-bath for30 minutes. The resulting solid was collected by filtration, washedsequentially with water, hexanes and ether (3×30 mL), and dried toafford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 2.06 (m,4H), 3.03 (m, 3H), 3.23 (m, 2H), 3.65 (s, 1H), 4.18 (s, 2H), 6.77 (ddd,J=2.6, 8.8, 9.6 Hz, 1H), 6.94 (dd, J=2.8, 9.6 Hz, 1H), 7.20 (dd, J=4.0,8.8 Hz, 1H); MS (ESI) m/z 231 (M+H)⁺.

Example 1629-fluoro-6-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (100 mg,0.434 mmol; Example 161) in a mixture of toluene (4 mL) and1,2-dimethoxyethane (1 mL) was degassed with nitrogen. n-Butyllithium (2M in cyclohexane; 217 mL, 0.434 mmol; Aldrich) was added at roomtemperature and the mixture stirred for 30 minutes.Bis(dibenzylidene-acetone)palladium (19.98 mg, 0.035 mmol; Aldrich),tri-tert-butylphosphine (1 M in toluene; 0.069 mL, 0.069 mmol; Aldrich)and (E)-5-(2-bromovinyl)-2-methylpyridine (86 mg, 0.434 mmol; Example23C) were added. The reaction mixture was heated at 70° C. for 18 hours.After cooling, the mixture was filtered through a pad of diatomaceousearth and concentrated in vacuo, and the residue was purified by flashchromatography (silica gel, Isco SF15-24, using a ofchloroform/methanol/concentrated NH₄OH, 90/9/1) to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ 2.20 (m, 4H), 2.55 (s, 3H),3.23 (m, 4H), 3.52 (m, 1H), 4.39 (s, 2H), 6.82 (d, J=14.5 Hz, 1H), 6.97(td, J=2.5, 9.0 Hz, 1H), 7.10 (dd, J=2.5, 9.0 Hz, 1H), 7.32 (d, J=8 Hz,1H), 7.64 (dd, J=4.0, 9.0 Hz, 1H), 7.72 (d, J=14.5 Hz, 1H), 7.99 (dd,J=2.3, 8.0 Hz, 1H), 8.55 (d, J=2.1 Hz, 1H); MS (ESI) m/z 348 (M+H)⁺.

Example 1639-fluoro-6-[2-(4-fluorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

General procedure C was used to convert1-(4-fluorophenethyl)-1-(4-fluorophenyl)-hydrazine (276 mg, 1.1 mmol;Example 85A) and 1-azabicyclo[3.2.2]nonan-4-one (144 mg, 1.1 mmol;Example 2A) into the title compound as the trifluoroacetic acid salt: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.60-1.77 (m, 2H) 1.96-2.15 (m, 2H) 2.92 (s,1H) 3.05 (t, J=6.54 Hz, 2H) 3.24 (d, J=28.16 Hz, 2H), 3.51-3.74 (m, 2H)4.31 (t, J=6.35 Hz, 2H) 4.57 (s, 2H) 6.81-6.89 (m, 2H) 6.89-6.95 (m, 2H)6.99-7.07 (m, 2H) 7.21-7.34 (m, 1H); MS (DCI/NH₃) m/z 353 (M+H)⁺.

Example 1646-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 164A9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex

A solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (3.5 g,15.2 mmol; Example 161) in tetrahydrofuran (30 mL) was chilled in an icebath under a dry nitrogen atmosphere and then borane tetrahydrofurancomplex (1.0 M; 16.7 mL, 16.7 mmol; Aldrich) was added slowly. After theaddition was complete, the ice bath was removed and the reaction mixturewas allowed to warm to room temperature and stir for 3 hours. Thevolatile components were removed under vacuum and the residue waspurified by flash chromatography (silica gel, 100% dichloromethane) toafford the title compound: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.04-2.35 (m,4H), 3.06 (s, 1H), 3.21-3.39 (m, 2H), 3.41-3.58 (m, 2H), 4.38 (s, 2H),6.86-6.95 (m, 1H), 7.01 (dd, J=9.2, 2.4 Hz, 1H), 7.23 (dd, J=8.9, 4.3Hz, 1H), 7.85 (brs, 1H); MS (ESI−) m/z 243 (M−H)⁻.

Example 164B6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (452 mg, 1.85 mmol; Example 164A) in tetrahydrofuran (5.0 mL)was added sodium amide (120 mg, 3.09 mmol; Aldrich) in portions. After30 minutes, 2-chloro-5-(chloromethyl)pyridine (250 mg, 1.5 mmol;Aldrich) was added and the solution was heated to 55° C. overnight. Thereaction was cooled to room temperature, quenched with water (5.0 mL),and then extracted with dichloromethane (2×10 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.73-2.00 (m, 4H),2.01-2.25 (m, 3H), 3.07 (s, 1H), 3.28 (d, J=7.1 Hz, 2H), 3.35-3.57 (m,2H), 4.41 (s, 2H), 5.31 (s, 2H), 6.89-7.01 (m, 1H), 7.03-7.17 (m, 3H),7.22 (s, 1H), 8.14 (d, J=2.4 Hz, 1H); MS (ESI−) m/z 368 (M−H)⁻.

Example 164C6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (420 mg, 1.18 mmol; Example 164B) in ethyl acetate (5.0mL) was treated with HCl (4 M in dioxane; 2 mL, 65.8 mmol; Aldrich) andthe mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo, and the residue was dissolved inwater (5 mL) and then basified (pH 10) with 4 M aqueous sodiumhydroxide. The mixture was concentrated in vacuo and the resultingmaterial was purified by flash chromatography [12 g silica gel, 0-100%gradient of CH₃OH-14.8 M-NH₄OH(aq) (10:1) in CH₂Cl₂] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.80-2.08 (m, 4H), 2.98-3.16 (m,2H), 3.17-3.37 (m, 2H), 3.49 (s, 1H), 4.26 (s, 2H), 5.28 (s, 2H),6.84-6.95 (m, 1H), 7.02-7.16 (m, 3H), 7.19-7.25 (m, 1H), 8.16 (s, 1H);MS (ESI)⁺ m/z 356 (M+H)⁺.

Example 164D6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoletartrate

The salt was prepared by dissolving the starting material from Example164C (275. mg, 0.775 mmol) in ethyl acetate (5.0 mL) and ethanol (1.0mL) then adding (2S,3S)-2,3-dihydroxysuccinic acid (128 mg, 0.852 mmol,dissolved in a minimal amount of methanol) slowly and stirring rapidlyover night. The material precipitated to give a white solid. The solidwas collected by filtration and dried under vacuum to give the titledcompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.97-2.13 (m, 2H)2.19-2.37 (m, 2H) 3.38-3.51 (m, 3H) 3.51-3.69 (m, 2H) 4.41 (s, 2H) 4.70(s, 2H) 5.54 (s, 2H) 6.89-7.05 (m, 1H) 7.18 (dd, J=9.32, 2.58 Hz, 1H)7.32-7.50 (m, 3H) 8.05 (s, 1H); MS (DCI/NH₃) m/z 356 (M+H)⁺. Anal.Calcd. for C₂₀H₁₉ClFN₃.C₄H₆O₆: C, 56.98; H, 4.97; 8.31. Found: C, 56.71;H, 4.88; N, 8.20.

Example 1659-fluoro-6-(4-fluorobenzyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 165A 1-(4-fluorobenzyl)-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (89 mg, 4.61 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) wasadded in portions. After 5 minutes the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and1-(bromomethyl)-4-fluorobenzene (0.416 mL, 3.38 mmol; Aldrich) was addeddropwise. After 30 minutes the ice bath was removed and the reaction washeated to 50° C. overnight. The mixture was diluted with water (5 mL),extracted with dichloromethane (2×10 mL) and the combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to afford the title product which was carried on withoutfurther purification: LC/MS (DCI/NH₃) m/z 218 (M+H-NH₃)⁺.

Example 165B9-fluoro-6-(4-fluorobenzyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of 1-(4-fluorobenzyl)-1-(4-fluorophenyl)hydrazine (500 mg,2.13 mmol; Example 165A) and 1-azabicyclo[3.2.2]nonan-4-one (446 mg, 3.2mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL) was heated at80° C. overnight. Water (20 mL) was added and the solution was basified(˜pH 10) by the addition of 4 M NaOH. The aqueous solution was extractedwith dichloromethane (2×10 mL) and the combined extracts wereconcentrated in vacuo and purified by reverse-phase HPLC (Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate 50mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.80-2.16 (m, 4H), 2.94 (s, 1H),3.08-3.24 (m, 2H), 3.27-3.45 (m, 2H), 4.38 (s, 2H), 5.24 (s, 2H),6.85-7.02 (m, 5H), 7.06 (dd, J=9.5, 2.4 Hz, 1H), 7.15 (dd, J=8.7, 4.4Hz, 1H); MS (ESI)⁺ m/z 339 (M+H)⁺.

Example 1666-(4-chlorobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 166A 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (202 mg, 4.92 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) wasadded in portions. After 5 minutes the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and1-(bromomethyl)-4-chlorobenzene (556 mg, 2.7 mmol; Aldrich) was addeddropwise. After 30 minutes, the ice bath was removed and the reactionwas heated to 50° C. overnight. The mixture was diluted with water (5mL) and extracted with dichloromethane (2×10 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to afford the title product which was carried on withoutfurther purification: LC/MS (DCI/NH₃) m/z 234 (M+H-NH₃)⁺.

Example 166B6-(4-chlorobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine (500 mg,1.99 mmol; Example 166A) and 1-azabicyclo[3.2.2]nonan-4-one (416 mg,2.99 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL) was heatedat 80° C. overnight. Water (20 mL) was added and the solution wasbasified (˜pH 10) by the addition of 4 M aqueous NaOH. The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.76-2.00 (m, 4H), 2.94 (s, 1H),3.01-3.14 (m, 2H), 3.18-3.30 (m, 2H), 4.26 (s, 2H), 5.25 (s, 2H),6.80-6.93 (m, 3H), 7.01-7.15 (m, 2H), 7.24 (d, J=8.2 Hz, 2H); MS(DCI/NH₃) m/z 355 (M+H)⁺.

Example 1676-(4-bromobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 167A 1-(4-bromobenzyl)-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (253 mg, 6.15 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) wasadded in portions. After 5 minutes the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and1-(bromomethyl)-4-bromobenzene (845 mg, 3.38 mmol; Aldrich) was addeddropwise. After 30 minutes the ice bath was removed and the reaction washeated to 50° C. overnight. The mixture was diluted with water (5 mL)and extracted with dichloromethane (2×10 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to afford the title product which was carried on withoutfurther purification: LC/MS (DCI/NH₃) m/z 279 (M+H-NH₃)⁺.

Example 167B6-(4-bromobenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of 1-(4-bromobenzyl)-1-(4-fluorophenyl)hydrazine (500 mg,1.69 mmol; Example 167A) and 1-azabicyclo[3.2.2]nonan-4-one (354 mg,2.54 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL) was heatedat 80° C. overnight. Water (20 mL) was added and the solution wasbasified (˜pH 10) by the addition of 4 M aqueous NaOH. The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.76-2.00 (m, 4H), 2.94 (s, 1H),3.01-3.14 (m, 2H), 3.18-3.30 (m, 2H), 4.26 (s, 2H), 5.25 (s, 2H), 6.81(d, J=8.5 Hz, 2H), 6.85-6.95 (m, 1H), 7.06 (dd, J=9.2, 2.4 Hz, 1H), 7.12(dd, J=8.8, 4.1 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H); MS (ESI)⁺ m/z 398.9(M+H)⁺.

Example 1689-fluoro-6-[3-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 168A 1-[(3-trifluoromethyl)benzyl]-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (189 mg, 4.61 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) wasadded in portions. After 5 minutes, the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and1-(bromomethyl)-3-trifluorobenzene (517 mg, 3.38 mmol; Aldrich) wasadded dropwise. After 30 minutes, the ice bath was removed and thereaction was heated to 50° C. overnight. The mixture was diluted withwater (5 mL) and extracted with dichloromethane (2×10 mL). The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford the title product which was carried onwithout further purification: MS (ESI+) m/z 265 (M+H-NH₃)⁺.

Example 168B9-fluoro-6-[3-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of 1-[(3-trifluoromethyl)benzyl]-1-(4-fluorophenyl)hydrazine(500 mg, 1.76 mmol; Example 168A) and 1-azabicyclo[3.2.2]nonan-4-one(364 mg, 2.64 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL)was heated at 80° C. overnight. Water (20 mL) was added and the solutionwas basified (˜pH 10) by the addition of 4 M aqueous NaOH. The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.76-2.00 (m, 4H), 2.94 (s, 1H),3.01-3.14 (m, 2H), 3.18-3.30 (m, 2H), 4.26 (s, 2H), 5.25 (s, 2H),6.86-6.96 (m, 1H), 7.01-7.16 (m, 3H), 7.30 (s, 1H), 7.39 (t, J=7.8 Hz,1H), 7.52 (d, J=7.8 Hz, 1H); MS (ESI)⁺ m/z 389 (M+H)⁺.

Example 1696-(2,3-difluoro-4-methylbenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 169A 1-(2,3-difluoro-4-methylbenzyl)-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.64 mmol; Aldrich) wasadded in portions. After 5 minutes, the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and1-(bromomethyl)-2,3-difluoro-4-methylbenzene (598 mg, 2.72 mmol;Aldrich) was added dropwise. After 30 minutes, the ice bath was removedand the reaction was heated to 50° C. overnight. The mixture was dilutedwith water (5 mL) and extracted with dichloromethane (2×10 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated in vacuo to afford the title product which was carriedon without further purification: LC/MS (DCI/NH₃) m/z 250 (M+H-NH₃)⁺.

Example 169B6-(2,3-difluoro-4-methylbenzyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of1-(2,3-difluoro-4-methylbenzyl)-1-(4-fluorophenyl)hydrazine (500 mg,1.65 mmol; Example 169A) and 1-azabicyclo[3.2.2]nonan-4-one (392 mg,2.82 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL) was heatedat 80° C. overnight. Water (20 mL) was added and the solution wasbasified (˜pH 10) by the addition of 4 M aqueous NaOH. The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.82-2.08 (m, 4H), 2.28 (s, 3H),2.95-3.17 (m, 3H), 3.18-3.38 (m, 2H), 4.28 (s, 2H), 5.30 (s, 2H), 6.16(t, J=7.1 Hz, 1H), 6.74 (t, J=7.0 Hz, 1H), 6.83-6.92 (m, 1H), 7.06 (dd,J=9.5, 2.4 Hz, 1H), 7.12 (dd, J=9.0, 4.2 Hz, 1H); MS (DCI/NH₃) m/z 371(M+H)⁺.

Example 1709-fluoro-6-[3-fluoro-4-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 170A1-(3-fluoro-4-trifluoromethylbenzyl)-1-(4-fluorophenyl)hydrazine

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (400 mg, 3.17 mmol; Aldrich) wasadded in portions. After 5 minutes, the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (598 mg, 2.33 mmol;Alfa Aesar) was added dropwise. After 30 minutes, the ice bath wasremoved and the reaction was heated to 50° C. overnight. The mixture wasdiluted with water (5 mL) and extracted with dichloromethane (2×10 mL).The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated in vacuo to afford the title product whichwas carried on without further purification: LC/MS (DCI/NH₃) m/z 250(M+H-NH₃)⁺.

Example 170B9-fluoro-6-[3-fluoro-4-(trifluoromethyl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of1-(3-fluoro-4-trifluoromethylbenzyl)-1-(4-fluorophenyl)hydrazine (500mg, 1.65 mmol; Example 170A) and 1-azabicyclo[3.2.2]nonan-4-one (392 mg,2.82 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL) was heatedat 80° C. overnight. Water (20 mL) was added and the solution wasbasified (˜pH 10) by the addition of 4M NaOH_((aq)). The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.77-1.95 (m, 2H), 1.94-2.13(m, 2H), 2.95-3.15 (m, 3H), 3.19-3.42 (m, 2H), 4.25 (s, 2H), 5.50 (s,2H), 6.76-6.99 (m, 3H), 7.08 (dd, J=9.5, 2.4 Hz, 1H), 7.19-7.41 (m, 1H),7.59 (t, J=7.9 Hz, 1H); MS (DCI/NH₃) m/z 407 (M+H)⁺.

Example 1719-fluoro-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 171A3-(4-((1-fluorophenyl)hydrazinyl)methyl)phenyl)-5-1,2,4-oxadiazole

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) wasadded in portions. After 5 minutes, the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and3-(4-(bromomethyl)phenyl)-5-methyl-1,2,4-oxadiazole (623 mg, 2.46 mmol;Alfa Aesar) was added dropwise. After 30 minutes, the ice bath wasremoved and the reaction was heated to 50° C. overnight. The mixture wasdiluted with water (5 mL) and extracted with dichloromethane (2×10 mL).The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated in vacuo to afford the title product whichwas carried on without further purification: LC/MS (DCI/NH₃) m/z 282(M+H-NH₃)⁺.

Example 171B9-fluoro-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of3-(4-((1-fluorophenyl)hydrazinyl)methyl)phenyl)-5-1,2,4-oxadiazole (500mg, 1.67 mmol; Example 171A) and 1-azabicyclo[3.2.2]nonan-4-one (392 mg,2.82 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL) was heatedat 80° C. overnight. Water (20 mL) was added and the solution wasbasified (˜pH 10) by the addition of 4 M NaOH. The aqueous solution wasextracted with dichloromethane (2×10 mL) and the combined extracts wereconcentrated in vacuo and purified by reverse-phase HPLC (Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate 50mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.82-2.08 (m, 4H), 2.64 (s, 3H),2.95-3.17 (m, 3H), 3.18-3.38 (m, 2H), 4.28 (s, 2H), 5.30 (s, 2H),6.96-7.07 (m, 2H), 7.64-7.72 (m, 1H), 7.82-7.91 (m, 1H), 7.98 (d, J=8.1Hz, 1H), 8.04-8.14 (m, 1H), 8.22 (d, J=5.4 Hz, 1H); MS (ESI)⁺ m/z 403(M+H)⁺.

Example 1729-fluoro-6-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 172A 4-((1-(4-fluorophenyl)hydrazinyl)methyl)-2-methylthiazole

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) wasadded in portions. After 5 minutes, the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and4-(bromomethyl)-2-methylthiazole (473 mg, 2.46 mmol; Aldrich) was addeddropwise. After 30 minutes, the ice bath was removed and the reactionwas heated to 50° C. overnight. The mixture was diluted with water (5mL) and extracted with dichloromethane (2×10 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to afford the title product which was carried on withoutfurther purification: LC/MS (DCI/NH₃) m/z 221 (M+H-NH₃)⁺.

Example 172B9-fluoro-6-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of 4-((1-(4-fluorophenyl)hydrazinyl)methyl)-2-methylthiazole(500 mg, 2.10 mmol; Example 172A) and 1-azabicyclo[3.2.2]nonan-4-one(392 mg, 2.82 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL)was heated at 80° C. overnight. Water (20 mL) was added and the solutionwas basified (˜pH 10) by the addition of 4M NaOH_((aq)). The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.77-1.95 (m, 2H), 1.94-2.13(m, 2H), 2.65 (s, 3H), 2.95-3.15 (m, 3H), 3.19-3.42 (m, 2H), 4.25 (s,2H), 5.50 (s, 2H), 6.67 (s, 1H), 6.79-6.90 (m, 1H), 7.02 (dd, J=9.5, 2.4Hz, 1H), 7.31 (dd, J=9.0, 4.2 Hz, 1H); MS (DCI/NH₃) m/z 343 (M+H)⁺.

Example 1739-fluoro-6-[(2-phenyl-1,3-oxazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 173A 4-((1-(4-fluorophenyl)hydrazinyl)methyl)-2-phenyloxazole

A flask containing tetrahydrofuran (2.0 mL) was charged with sodiumamide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C.(4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) wasadded in portions. After 5 minutes, the solid had completely dissolvedand the ice bath was removed. Stirring was continued for 1 hour, thenthe solution was chilled again in an ice bath and4-(bromomethyl)-2-phenyloxazole (586 mg, 2.46 mmol; Anichem) was addeddropwise. After 30 minutes, the ice bath was removed and the reactionwas heated to 50° C. overnight. The mixture was diluted with water (5mL) and extracted with dichloromethane (2×10 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to afford the title product which was carried on withoutfurther purification: LC/MS (DCI/NH₃) m/z 267 (M+H-NH₃)⁺.

Example 173B9-fluoro-6-[(2-phenyl-1,3-oxazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of 4-((1-(4-fluorophenyl)hydrazinyl)methyl)-2-phenyloxazole(500 mg, 1.67 mmol; Example 173A) and 1-azabicyclo[3.2.2]nonan-4-one(392 mg, 2.82 mmol; Example 2A) in 7% sulfuric acid in dioxane (10 mL)was heated at 80° C. overnight. Water (20 mL) was added and the solutionwas basified (˜pH 10) by the addition of 4 M aqueous NaOH. The aqueoussolution was extracted with dichloromethane (2×10 mL) and the combinedextracts were concentrated in vacuo and purified by reverse-phase HPLC(Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column, 30×75 mm, 10-95%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the trifluoroacetic acidsalt: LC/MS (DCI/NH₃) m/z 388 (M+H)⁺.

Example 1749-bromo-6-[2-(4-chlorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 174A9-bromo-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of HCl in acetic acid (1 M, 30 mL) was added under nitrogento a mixture of 4-bromophenylhydrazine hydrochloride (4.33 g, 19.37mmol; Aldrich) and 1-azabicyclo[3.2.2]nonan-4-one (2.70 g, 19.37 mmol;Example 2A). The mixture was stirred at room temperature for 16 hours,then heated at 75° C. for 3 hours. The mixture was cooled to roomtemperature and concentrated under vacuum to remove most of the aceticacid. Anhydrous ethanol (100 mL) was added to the residue, and themixture was heated at reflux for 10 minutes, then cooled to roomtemperature. The precipitate was collected by filtration, washed withethanol (25 mL) and dried under vacuum to provide the title compound asits HCl salt (3.02 g). A portion of this salt (400 mg) was partitionedbetween 20% NaOH (25 mL) and chloroform (50 mL) and the organic phasewas dried (sodium sulfate) and concentrated. The residue wascrystallized from ethyl acetate-ethanol (5:1) to provide the free baseof title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 2.14-2.36 (m,4H), 3.17-3.25 (m, 1H), 3.33-3.45 (m, 2H), 3.45-3.65 (m, 2H), 4.54 (s,2H), 7.18 (dd, J=8.8, 1.8 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 7.51 (d,J=2.4 Hz, 1H); MS (DCI) m/z 291/293 (M+H)⁺.

Example 174B9-bromo-6-[2-(4-chlorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Sodium dispersion in paraffin (30%; 162 mg, 2.11 mmol; Aldrich) wascombined with9-bromo-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (290 mg,0.996 mmol; Example 174A) in a 20 mL vial with stir bar and septum cap.Dimethyl sulfoxide (4.0 mL) was added, and the vial was evacuated andpurged with nitrogen (10 cycles). The mixture was stirred at roomtemperature for 30 minutes, and a solution of 4-chlorostyrene (213 mg,1.54 mmol; Aldrich) and hydroquinone (53 mg, 0.48 mmol; Aldrich) indimethyl sulfoxide (2 mL) was added. The vial was evacuated and purgedwith nitrogen (5 cycles) and the mixture was stirred with heating at105° C. for 110 hours. The mixture was cooled to room temperature,diluted with water (100 mL) and 25% NaOH (2 mL) and extracted withchloroform (3×50 mL). The combined organic phase was concentrated andthe residue was purified by flash chromatography (silica, eluted withCHCl₃—CH₃OH-14.8 M aqueous NH₄OH (90:10:1). The product-containingfractions were combined and concentrated under vacuum to provide aresidue (140 mg), which was further purified by reverse-phase HPLC[Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute,40-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]to provide the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.60-1.74(m, 2H), 1.81-1.97 (m, 2H), 2.80-2.88 (m, 1H), 2.97 (t, J=6.8 Hz, 2H),3.00-3.08 (m, 2H), 3.25 (ddd, J=14.1, 9.0, 5.4 Hz, 2H), 4.20-4.31 (m,2H), 4.24 (s, 2H), 6.88-6.94 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 7.21 (d,J=7.1 Hz, 1H), 7.20-7.25 (m, 2H), 7.50 (d, J=1.7 Hz, 1H); MS (DCI) m/z429/431/433 (M+H)⁺.

Example 1759-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

In a 30 mL microwave reaction tube were combined4-(trifluoromethoxy)phenylhydrazine hydrochloride (1143 mg, 5.0 mmol;Alfa Aesar), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid(15 mL). The reaction mixture was heated in a microwave to 150° C.(Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooledto room temperature. The solvent was removed, and the residue wasbasified with 5 N sodium hydroxide and extracted with ethyl acetate(3×50 mL). The combined organic phases were concentrated in vacuo andpurified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm,30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer(0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammoniumhydroxide) over 20 minutes] to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 2.08 (td, J=7, 4 Hz, 4H), 2.99-3.13 (m, 3H),3.23 (dd, J=14, 7 Hz, 2H), 4.21 (s, 2H), 6.92 (ddd, J=9, 2, 1 Hz, 1H),7.16 (d, J=1 Hz, 1H), 7.28 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 297 (M+H)⁺.

Example 1766-[(E)-2-pyridin-3-ylvinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(140 mg, 0.473 mmol; Example 175) and 3-ethynylpyridine (97 mg, 0.945mmol; Aldrich) was performed according to the procedure described inExample 20 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δppm 2.09-2.18 (m, 4H), 3.03-3.16 (m, 2H), 3.19-3.29 (m, 2H), 3.42-3.49(m, 1H), 4.25 (s, 2H), 6.86 (d, J=14 Hz, 1H), 7.10 (ddd, J=9, 2, 1 Hz,1H), 7.28 (d, J=1 Hz, 1H), 7.45 (dd, J=8, 5 Hz, 1H), 7.72 (d, J=9 Hz,1H), 7.79 (d, J=15 Hz, 1H), 8.10 (dt, J=8, 2 Hz, 1H), 8.43 (dd, J=5, 2Hz, 1H), 8.71 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 400 (M+H)⁺.

Example 1776-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(140 mg, 0.473 mmol; Example 175) and 5-ethynyl-2-methylpyridine (111mg, 0.945 mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δppm 1.66-1.80 (m, 2H), 1.84-1.98 (m, 2H), 2.40 (s, 3H), 2.95-3.23 (m,5H), 4.24 (s, 2H), 6.83 (d, J=8 Hz, 1H), 6.92-6.99 (m, 2H), 7.06-7.16(m, 3H), 7.28 (s, 1H), 7.85 (s, 1H); MS (DCI/NH₃) m/z 414 (M+H)⁺.

Example 1786-[2-(6-methylpyridin-3-yl)ethyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(65 mg, 0.157 mmol; Example 177) in methanol was treated with platinumoxide under a hydrogen atmosphere (1 atm) at 40° C. for 16 hours toafford the title compound as the major product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.57-1.71 (m, 2H), 1.86-2.00 (m, 2H), 2.40 (s, 3H),2.89-3.21 (m, 7H), 4.16 (s, 2H), 4.42 (t, J=6 Hz, 2H), 6.93 (ddd, J=9,2, 1 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 7.18 (d, J=1 Hz, 1H), 7.25 (d, J=9Hz, 1H), 7.31 (dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH₃)m/z 416 (M+H)⁺.

Example 1796-[2-(6-methylpiperidin-3-yl)ethyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(65 mg, 0.157 mmol; Example 177) in methanol was treated with platinumoxide under a hydrogen atmosphere (1 atm) at 40° C. for 16 hours toafford the title compound as the minor product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.02-1.14 (m, 3H), 1.46-1.86 (m, 4H), 1.98-2.21 (m,4H), 2.64-2.79 (m, 2H), 2.96-3.12 (m, 3H), 3.17-3.28 (m, 3H), 4.15-4.25(m, 4H), 6.99 (ddd, J=9, 2, 1 Hz, 1H), 7.19 (s, 1H), 7.33-7.40 (m, 1H);MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 1809-(methylsulfonyl)-3,4,5,6-tetrahydro-H-2,5-ethanoazepino[4,3-b]indole

A mixture of (4-(methylsulfonyl)phenyl)hydrazine hydrochloride (1105 mg,5.0 mmol; Acros), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol;Example 2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and aceticacid (15 mL) was heated to 80° C. overnight (16 hours), then cooled toroom temperature. The solvent was removed, and the residue was basifiedwith 5 N aqueous sodium hydroxide and extracted with ethyl acetate (3×50mL). The combined organic phases were concentrated in vacuo and purifiedby reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm,flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 20 minutes] to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 2.05-2.14 (m, 4H), 3.02-3.15 (m, 6H), 3.20-3.28 (m,2H), 4.29 (s, 2H), 7.47 (d, J=8 Hz, 1H), 7.57-7.62 (m, 1H), 7.95 (d, J=1Hz, 1H); MS (DCI/NH₃) m/z 291 (M+H)⁺.

Example 1816-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The coupling of9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(150 mg, 0.517 mmol; Example 180) and 5-ethynyl-2-methylpyridine (182mg, 1.55 mmol; prepared as described in International Publication No.WO2005090333) was performed according to the procedure described inExample 20 to afford the title compound as the major product: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.70-1.82 (m, 2H), 1.88-2.01 (m, 2H), 2.40(s, 3H), 2.96-3.24 (m, 5H), 3.10 (s, 3H), 4.32 (s, 2H), 6.91 (d, J=8 Hz,1H), 7.00 (d, J=8 Hz, 1H), 7.09 (s, 2H), 7.32 (d, J=9 Hz, 1H), 7.61 (dd,J=9, 2 Hz, 1H), 7.87 (s, 1H), 8.04 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 408(M+H)⁺.

Example 1826-[2-(6-methylpyridin-3-yl)ethyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(20 mg, 0.049 mmol; Example 181) in methanol was treated with platinumoxide under a hydrogen atmosphere (1 atm) at 40° C. for 16 hours toafford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.62-1.76(m, 2H), 1.90-2.05 (m, 2H), 2.40 (s, 3H), 2.91-3.24 (m, 10H), 4.26 (s,2H), 4.49 (t, J=6 Hz, 2H), 7.11 (d, J=8 Hz, 1H), 7.34 (dd, J=8, 2 Hz,1H), 7.42 (d, J=9 Hz, 1H), 7.59 (dd, J=9, 2 Hz, 1H), 7.84 (d, J=2 Hz,1H), 7.95 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z 410 (M+H)⁺.

Example 1839-fluoro-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 183A9-fluoro-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (452 mg, 1.85 mmol; Example 164A) in tetrahydrofuran (5.0 mL)was added sodium amide (120 mg, 3.09 mmol; Aldrich) in portions. After30 minutes, 5-(chloromethyl)-2-(trifluoromethyl)pyridine (250 mg, 1.278mmol; Aldrich) was added and the solution was heated to 55° C.overnight. The reaction was cooled to room temperature and quenched withwater (5.0 mL), then extracted with dichloromethane (2×10 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure to provide the titled compound.The resulting material was carried on to the next step without furtherpurification: LC/MS (DCI/NH₃) m/z 390 (M+H-BH₃)⁺.

Example 183B9-fluoro-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of9-fluoro-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (515 mg, 1.278 mmol; Example 183B) in ethyl acetate(5.0 mL) was treated with HCl (4 M in dioxane; 2 mL, 65.8 mmol; Aldrich)and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo, and the residue dissolved in water (5mL) and then basified (pH 10) with 4 M aqueous sodium hydroxide. Themixture was concentrated in vacuo and the resulting material waspurified by flash chromatography [12 g silica gel, 0-100% gradient ofCH₃OH-14.8 M aqueous NH₄OH (9:1) in CH₂Cl₂] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.86-2.20 (m, 4H), 3.05 (s, 1H),3.08-3.27 (m, 2H), 3.30-3.55 (m, 2H), 4.40 (s, 2H), 5.41 (s, 2H),6.88-6.99 (m, 1H), 7.05-7.15 (m, 2H), 7.30 (d, J=6.7 Hz, 1H), 7.59 (d,J=7.5 Hz, 1H), 8.49 (s, 1H); MS (ESI+) m/z 390 (M+H)⁺.

Example 1849-fluoro-6-(pyridin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (244 mg, 1.0 mmol; Example 164A) in tetrahydrofuran (5.0 mL) wasadded sodium hydride (60% dispersion in mineral oil; 80 mg, 2.0 mmol;Aldrich) in one portion. After stirring for 30 minutes,2-(chloromethyl)pyridine hydrochloride (197 mg, 1.2 mmol; Aldrich) wasadded and the solution was heated to 55° C. overnight. After the solventwas removed, the residue was treated with HCl in acetone/water (1 N,acetone:water=3:1, 5 mL) and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated in vacuo, and theresidue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanolin buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 20 minutes] to afford the title compound: ¹HNMR (300 MHz, methanol-d₄) δ ppm 1.82-2.06 (m, 4H), 2.98-3.26 (m, 5H),4.23 (s, 2H), 5.47 (s, 2H), 6.67 (d, J=8 Hz, 1H), 6.85 (td, J=9, 3 Hz,1H), 7.05 (dd, J=9, 2 Hz, 1H), 7.27 (dd, J=9, 4 Hz, 2H), 7.67 (td, J=8,2 Hz, 1H), 8.51 (ddd, J=5, 2, 1 Hz, 1H); MS (DCI/NH₃) m/z 322 (M+H)⁺.

Example 1859-fluoro-6-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (244 mg, 1.0 mmol; Example 164A) in tetrahydrofuran (5.0 mL) wasadded sodium hydride (60% dispersion in mineral oil; 80 mg, 2.0 mmol;Aldrich) in one portion. After stirring for 30 minutes,3-(chloromethyl)pyridine hydrochloride (197 mg, 1.2 mmol; Alfa Aesar)was added and the solution was heated to 55° C. overnight. After thesolvent was removed, the residue was treated with HCl in acetone/water(1 N, acetone:water=3:1, 5 mL) and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated in vacuo,and the residue was purified by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.79-1.92 (m, 2H),1.94-2.08 (m, 2H), 2.98-3.10 (m, 2H), 3.12-3.25 (m, 3H), 4.23 (s, 2H),5.48 (s, 2H), 6.87 (td, J=9, 2 Hz, 1H), 7.06 (dd, J=9, 2 Hz, 1H),7.27-7.40 (m, 3H), 8.21 (d, J=1 Hz, 1H), 8.40 (dd, J=5, 2 Hz, 1H); MS(DCI/NH₃) m/z 322 (M+H)⁺.

Example 1869-fluoro-6-(pyridin-4-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (244 mg, 1.0 mmol; Example 164A) in tetrahydrofuran (5.0 mL) wasadded sodium hydride (60% dispersion in mineral oil; 80 mg, 2.0 mmol;Aldrich) in one portion. After stirring for 30 minutes,4-(chloromethyl)pyridine hydrochloride (197 mg, 1.2 mmol; Aldrich) wasadded and the solution was heated to 55° C. overnight. After the solventwas removed, the residue was treated with HCl in acetone/water (1 N,acetone:water=3:1, 5 mL) and the mixture was stirred at room for 2hours. The reaction mixture was concentrated in vacuo, and the residuewas purified by reverse-phase HPLC [Waters XBridge™ C 18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanolin buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 20 minutes] to afford the title compound: ¹HNMR (300 MHz, methanol-d₄) δ ppm 1.83-2.06 (m, 4H), 2.99-3.11 (m, 3H),3.15-3.25 (m, 2H), 4.24 (s, 2H), 5.48 (s, 2H), 6.85 (td, J=9, 2 Hz, 1H),6.97 (d, J=6 Hz, 2H), 7.07 (dd, J=10, 2 Hz, 1H), 7.23 (dd, J=9, 4 Hz,1H), 8.39-8.43 (m, 2H). MS (DCI/NH₃) m/z=322 (M+H)⁺.

Example 1876-[(pyridin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 187A 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Phenylhydrazine hydrochloride (10.0 g, 69.2 mmol) and1-azabicyclo[3.2.2]nonan-4-one (9.63 g, 69.2 mmol; Example 2A) weredissolved in 7% (v/v) concentrated H₂SO₄ in dioxane (150 mL). Thereaction mixture was heated to 80° C. overnight. H₂O (250 mL) was added.The reaction mixture was made basic (pH 12) by the addition of 4 Maqueous NaOH. The resulting precipitate was filtered then washed withH₂O (50 mL) followed by hexanes (50 mL) to give the titled compound: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.88-2.22 (m, 4H), 2.93 (s, 1H), 2.99-3.20(m, 2H), 3.21-3.43 (m, 2H), 4.29 (s, 2H), 7.04-7.17 (m, 2H), 7.28-7.33(m, 1H), 7.38 (d, J=8.3 Hz, 1H); MS (DCI/NH₃) m/z 213 (M+H)⁺.

Example 187B 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex

A suspension of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(2.4 g, 11.45 mmol) in tetrahydrofuran (20 mL) was treated with 1 M BH₃in tetrahydrofuran (14.8 mL; Aldrich), which was added dropwise over 15minutes. After 3 hours, the reaction mixture was concentrated in vacuoand purified by silica gel chromatography (eluting with CH₂Cl₂) toafford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.16 (m, 3H),3.05 (m, 1H), 3.30 (m, 2H), 3.49 (m, 2H), 3.72 (m, 1H), 4.45 (s, 2H),7.15 (m, 2H), 7.33 (m, 2H), 7.84 (br s, 1H); MS (ESI) m/z 225 (M−H)⁻,453 (2M+H)⁺.

Example 187C6-[(pyridin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (113 mg, 0.5 mmol; Example 187B) in tetrahydrofuran(3.0 mL) was added sodium hydride (60% dispersion in mineral oil; 40 mg,1.0 mmol; Aldrich) in one portion. After stirring for 30 minutes,2-(chloromethyl)pyridine hydrochloride (99 mg, 0.6 mmol; Aldrich) wasadded and the solution was heated to 55° C. overnight. After the solventwas removed, the residue was treated with HCl in acetone/water (1 N,acetone:water=3:1, 5 mL) and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated in vacuo, and theresidue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanolin buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 20 minutes] to afford the title compound: ¹HNMR (300 MHz, methanol-d₄) δ ppm 1.82-2.05 (m, 4H), 2.99-3.25 (m, 5H),4.28 (s, 2H), 5.48 (s, 2H), 6.63 (d, J=8 Hz, 1H), 7.00-7.13 (m, 2H),7.23-7.32 (m, 2H), 7.38 (d, J=7 Hz, 1H), 7.65 (td, J=8, 2 Hz, 1H), 8.51(ddd, J=5, 2, 1 Hz, 1H); MS (DCI/NH₃) m/z 304 (M+H)⁺.

Example 1886-(pyridin-3-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (113 mg, 0.5 mmol; Example 187B) in tetrahydrofuran(3.0 mL) was added sodium hydride (60% dispersion in mineral oil; 40 mg,1.0 mmol; Aldrich) in one portion. After stirring for 30 minutes,3-(chloromethyl)pyridine hydrochloride (99 mg, 0.6 mmol; Alfa Aesar) wasadded and the solution was heated to 55° C. overnight. After the solventwas removed, the residue was treated with HCl in acetone/water (1 N,acetone:water=3:1, 5 mL) and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated in vacuo, and theresidue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanolin buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 20 minutes]. This material was purified furtherby reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 5-95% gradient of methanol in 0.1% aqueoustrifluoroacetic acid over 20 minutes) to afford the title compound asthe bistrifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm1.83-1.92 (m, 2H), 1.97-2.08 (m, 2H), 3.30-3.45 (m, 3H), 3.71 (ddd,J=14, 9, 5 Hz, 2H), 4.87 (s, 2H), 5.50 (s, 2H), 7.17 (dd, J=8, 5 Hz,1H), 7.25-7.30 (m, 2H), 7.33 (t, J=8 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.54(d, J=8 Hz, 1H), 8.62 (d, J=2 Hz, 1H), 8.66 (d, J=4 Hz, 1H); MS(DCI/NH₃) m/z 304 (M+H)⁺.

Example 1896-[(pyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (113 mg, 0.5 mmol; Example 187B) in tetrahydrofuran(3.0 mL) was added sodium hydride (60% dispersion in mineral oil; 40 mg,1.0 mmol; Aldrich) in one portion. After stirring for 30 minutes,4-(chloromethyl)pyridine hydrochloride (99 mg, 0.6 mmol; Aldrich) wasadded and the solution was heated to 55° C. overnight. After the solventwas removed, the residue was treated with HCl in acetone/water (1 N,acetone:water=3:1, 5 mL) and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated in vacuo, and theresidue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanolin buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 20 minutes] to afford the title compound: ¹HNMR (300 MHz, methanol-d₄) δ ppm 1.83-2.06 (m, 4H), 3.00-3.13 (m, 3H),3.14-3.25 (m, 2H), 4.29 (s, 2H), 5.49 (s, 2H), 6.98 (d, J=6 Hz, 2H),7.01-7.14 (m, 2H), 7.26 (d, J=8 Hz, 1H), 7.39 (d, J=7 Hz, 1H), 8.37-8.43(m, 2H); MS (DCI/NH₃) m/z 304 (M+H)⁺.

Example 1908-[(6-chloropyridin-3-yl)methyl]-1-fluoro-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indoleExample 190A 2-chloro-5-{[1-(4-fluorophenyl)hydrazino]methyl}pyridine

A mixture of (4-fluorophenyl)hydrazine hydrochloride (2.52 g, 20 mmol;Aldrich) and 2-chloro-5-(chloromethyl)pyridine (3.24 g, 20.00 mmol;Aldrich) in ethanol (120 mL) was treated with triethylamine (9.76 mL,70.0 mmol; Aldrich), and the mixture was heated at 80° C. with stirringfor 16 hours. The solvent was removed and the residue was purified byflash chromatography (silica gel, 10:1 CH₂Cl₂—CH₃OH) to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 4.53 (s, 2H), 6.93-6.99(m, 2H), 7.02-7.10 (m, 2H), 7.40 (d, J=8 Hz, 1H), 7.77 (dd, J=8, 3 Hz,1H), 8.30 (d, J=3 Hz, 1H); MS (DCI/NH₃) m/z 252 (M+H)⁺.

Example 190B 1-azatricyclo[4.3.1.1^(3,8)]undecan-4-one

To an ice-cooled solution of trimethylsilyldiazomethane (2 N in hexanes,9.00 mL, 18.00 mmol; Aldrich) was added a solution of1-azaadamantan-4-one (2.268 g, 15 mmol; Becker, D. P.; Flynn, D. L.Synthesis 1992, 1080) in tetrahydrofuran (12 mL) dropwise over 20minutes. Anhydrous methanol (6 mL) was added and the mixture was allowedto warm to room temperature. After 18 hours, glacial acetic acid wasadded dropwise until the mixture was colorless (about 1 mL). Thereaction mixture was shaken with saturated sodium carbonate (4 mL), thetetrahydrofuran layer was separated, and the aqueous portion wasextracted with dichloromethane (3×12 mL). The combined organic phaseswere dried over magnesium sulfate, filtered, and concentrated to givethe title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.72 (m, 1H), 1.78(dddd, J=13.6, 4.0, 2.4, 2.1 Hz, 1H), 1.88 (m, 1H), 1.90 (dddd, J=14.6,4.0, 2.4, 2.1 Hz, 1H), 2.14 (dddd, J=14.4, 6.5, 4.4, 1.9 Hz, 1H), 2.27(m, 1H), 2.59 (t, J=5.8 Hz, 1H), 2.63-2.68 (m, 2H), 2.96 (m, 1H), 3.01(dd, J=4.4, 2.0 Hz, 1H), 3.07 (m, 1H), 3.14 (m, 1H), 3.25 (ddd, J=14.6,4.9, 1.2 Hz, 1H), 3.43 (dd, J=14.2, 5.1 Hz, 1H); MS (DCI/NH₃) m/z 166(M+H)⁺.

Example 190C8-[(6-chloropyridin-3-yl)methyl]-1-fluoro-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

A solution of 2-chloro-5-{[1-(4-fluorophenyl)hydrazino]methyl}pyridine(252 mg, 1.0 mmol; Example 190A) and1-azatricyclo[4.3.1.1^(3,8)]undecan-4-one (165 mg, 1.0 mmol; Example190B) in dry dioxane (8 mL) was treated with concentrated sulfuric acid(0.107 mL, 2.0 mmol; J. T. Baker), and the mixture was heated to 100° C.with stirring for 16 hours. The mixture was cooled, concentrated,basified with 1 N aqueous sodium hydroxide, and extracted withdichloromethane (3×50 mL). The combined organic phase was concentratedin vacuo and then purified by reverse-phase HPLC [Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.81-2.03 (m, 3H), 2.19(dt, J=13, 5 Hz, 1H), 2.26-2.36 (m, 1H), 2.95 (ddd, J=16, 5, 5 Hz, 2H),3.09-3.27 (m, 4H), 3.30-3.38 (m, 1H), 3.43 (dd, J=13, 4 Hz, 1H), 5.43(s, 2H), 6.82 (td, J=9, 3 Hz, 1H), 7.08 (dd, J=10, 2 Hz, 1H), 7.26 (dd,J=9, 4 Hz, 1H), 7.29-7.39 (m, 2H), 8.00 (d, J=1 Hz, 1H). MS (DCI/NH₃)m/z=382/384 (M+H)⁺.

Example 1919-fluoro-6-[(2-fluoropyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 191A9-fluoro-6-[(2-fluoropyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (385 mg, 1.579 mmol; Example 164A) in tetrahydrofuran (5.0 mL)was added sodium amide (103 mg, 2.63 mmol; Aldrich) in portions. After30 minutes, 4-(bromomethyl)-2-fluoropyridine (250 mg, 1.316 mmol;Biogene Organics) was added and the solution was heated to 55° C.overnight. The reaction was cooled to room temperature and quenched withwater (5.0 mL), then extracted with dichloromethane (2×10 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure to provide the titled compound.The resulting material was carried on to the next step without furtherpurification: LC/MS (DCI/NH₃) m/z 340 (M+H-BH₃)⁺.

Example 191B9-fluoro-6-[(2-fluoropyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A solution of9-fluoro-6-[(2-fluoropyridin-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (447 mg, 1.316 mmol; Example 191A) in ethyl acetate(5.0 mL) was treated with HCl (4 M in dioxane; 2 mL, 65.8 mmol; Aldrich)and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo, and the residue dissolved in water (5mL) and then basified (pH 10) with 4 M aqueous sodium hydroxide. Themixture was concentrated in vacuo and the resulting material waspurified by flash chromatography [12 g silica gel, 0-100% gradient ofCH₃OH-14.8 M aqueous NH₄OH (9:1) in CH₂Cl₂] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.78-2.08 (m, 4H), 2.82-2.97 (m,1H), 3.00-3.18 (m, 2H), 3.20-3.36 (m, 2H), 4.28 (s, 2H), 5.30 (s, 2H),6.47 (s, 1H), 6.77 (d, J=5.2 Hz, 1H), 6.84-6.95 (m, 1H), 7.00-7.13 (m,2H), 8.14 (d, J=5.6 Hz, 1H); MS (ESI+) m/z=340 (M+H)⁺.

Example 19211-methyl-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

In a 50 mL round-bottom flask were combined p-tolylhydrazinehydrochloride (0.753 g, 4.74 mmol; Aldrich), and1-azatricyclo[4.3.1.1^(3,8)]undecan-4-one (0.784 g, 4.74 mmol; Example190B) in dioxane (18 mL). After 10 minutes, the suspension cleared.Concentrated sulfuric acid (1.265 mL, 23.72 mmol) was added and themixture was heated at 80° C. After 1.5 hours, the mixture was cooled andconcentrated to about 3 mL. The residue was dissolved in water (75 mL),basified with concentrated sodium hydroxide (30 mmol), extracted withchloroform (4×25 mL), dried over magnesium sulfate, and concentrated.The resulting material was purified by flash chromatography (Analogix 15mm 12 g silica gel column, eluted with a 10-30% gradient of methanol inchloroform) to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.97 (d, J=13.2 Hz, 1H), 2.03-2.13 (m, 2H), 2.21-2.34 (m, 2H),2.37 (s, 3H), 2.86 (t, J=5.1 Hz, 1H), 3.06 (t, J=5.1 Hz, 1H), 3.22 (d,J=13.2 Hz, 1H), 3.28-3.34 (m, 3H), 3.48 (td, J=13.0, 4.6 Hz, 2H), 6.82(ddd, J=8.1, 1.2 Hz, 1H), 7.11 (dd, J=1.2, 0.7 Hz, 1H), 7.12 (d, J=8.1Hz 1H); MS (DCI/NH₃) m/z 253 (M+H)⁺.

Example 19311-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indoleExample 193A11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

A reaction flask with a septum cap was charged with 30% sodium metaldispersion in paraffin wax (0.14 g, 1.86 mmol; Aldrich) and a solutionof11-methyl-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole(0.30 g, 1.33 mmol; Example 192) in dimethyl sulfoxide (6 mL). Thevessel was sealed, flushed with nitrogen, and stirred for 10 minutes. Asolution of 2-methyl-5-vinylpyridine (0.24 g, 1.99 mmol; prepared asdescribed in International Publication No. WO 2001017968) andhydroquinone (0.036 g, 0.33 mmol; Aldrich) in anhydrous dimethylsulfoxide (1.5 mL) was added and the reaction mixture was heated at 100°C. for 72 hours. After cooling the reaction mixture to room temperature,it was poured into water and extracted with ethyl acetate (4×25 mL). Thecombined organic extracts were washed with brine, concentrated, andpurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile inbuffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 15 minutes] to afford the title compound.

Example 193B11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indolehydrochloride

A solution of11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole(93 mg, 0.25 mmol; Example 193A) in ethyl acetate (1.5 mL) was treatedwith a solution of HCl in dioxane (4 M, 0.063 mL, 0.25 mmol; Aldrich),added dropwise. After stirring for 20 minutes, the solid was collectedby filtration, rinsed with ethyl acetate, and dried for 10 hours at 75°C. under high vacuum to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.49 (d, J=13.9 Hz, 1H), 1.88 (d, J=13.6 Hz, 1H),2.10 (dt, J=13.6, 5.3 Hz, 1H), 2.28 (dt, J=13.6, 4.9 Hz, 1H), 2.38 (m,1H), 2.41 (s, 3H), 2.44 (s, 3H), 2.86 (d, J=12.5 Hz, 1H), 3.05 (t, J=6.4Hz, 2H), 3.20 (t, J=5.6 Hz, 1H), 3.33 (d, J=12.5 Hz, 1H), 3.46 (t, J=5.1Hz, 1H), 3.51-3.62 (m, 4H), 3.77 (dd, J=12.7, 4.6 Hz, 1H), 4.40 (td,J=6.4, 3.1 Hz, 2H), 6.97 (dd, J=8.3, 1.5 Hz, 1H), 7.16 (d, J=7.8 Hz,1H), 7.20 (d, J=8.4 Hz, 1H), 7.22 (d, J=1.3 Hz, 1H), 7.34 (dd, J=7.8,2.4 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H); MS (DCI/NH₃) m/z 372.2 (M+H)⁺.

Example 194(1R*,7R*,7aS*,12bR*)-11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,7a,8,12b-octahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

A solution of the product of Example 193 (94 mg, 0.253 mmol) intrifluoroacetic acid (0.8 mL) was cooled to 4° C. and was treated with asolution of sodium cyanoborohydride (80 mg, 1.265 mmol) in anhydrousmethanol (0.2 mL). The mixture was warmed to room temperature for 1hour, then concentrated. The residue was taken up in water (1 mL) andstirred for 45 minutes. The mixture was purified by reverse-phase HPLC[Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute,5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15 minutes]to provide a mixture of diastereomers (45 mg). The diastereomers wereseparated by flash chromatography (Analogix 10 mm 4 g silica gel column,eluted with 5-10% 14.8 M aqueous NH₄OH—CH₃OH (1:20) in CHCl₃) to affordthe title compound (Rf thin-layer chromatography 0.44 (20% CH₃OH/1% 14.8M aqueous NH₄OH/79% CH₂Cl₂): ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.67(br d, J=14.0 Hz, 1H), 1.78 (br d, J=14.0 Hz, 1H), 1.79 (m, 1H), 2.14(m, 1H), 2.19 (s, 3H), 2.20 (m, 1H), 2.25 (m, 1H), 2.28 (m, 1H), 2.48(s, 3H), 2.52 (br d, J=14.0 Hz, 1H), 2.76 (ddd, J=14.5, 8.9, 6.1 Hz,1H), 2.87 (ddd, J=15.1, 9.2, 6.3 Hz, 1H), 2.90 (br d, J=14.0 Hz, 1H),2.95 (m, 3H), 3.05 (d, J=13.7 Hz, 1H), 3.21 (ddd, J=14.8, 8.9, 6.0 Hz,1H), 3.46 (ddd, J=14.8, 9.1, 6.0 Hz, 1H), 3.67 (dd, J=11.4, 2.6 Hz, 1H),3.88 (dd, J=11.4, 4.7 Hz, 1H), 6.32 (d, J=7.9 Hz, 1H), 6.72 (s, 1H),6.82 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.60 (dd, J=8.0, 2.3 Hz,1H), 8.24 (d, J=1.8 Hz, 1H); MS (DCI/NH₃) m/z 374.3 (M+H)⁺.

Example 195(1R*,7R*,7aR*,12bS*)-11-methyl-8-[2-(6-methylpyridin-3-yl)ethyl]-1,4,5,6,7,7a,8,12b-octahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

Purification of the mixture of Example 194 by flash chromatography asdescribed in Example 194 afforded the title compound (Rf thin-layerchromatography 0.57 (20% CH₃OH/1% 14.8 M aqueous NH₄OH/79% CH₂Cl₂): ¹HNMR (500 MHz, methanol-d₄) δ ppm 1.39 (br d, J=13.8 Hz, 1H), 1.50 (m,1H), 1.75 (m, 1H), 1.79 (m, 1H), 1.91 (br d, J=13.8 Hz, 1H), 2.14 (m,1H), 2.16 (m, 1H), 2.18 (s, 3H), 2.47 (s, 3H), 2.76 (ddd, J=14.6, 8.9,6.1 Hz, 1H), 2.86 (ddd, J=15.0, 9.1, 6.3 Hz, 1H), 2.88 (d, J=14.0 Hz,1H), 2.93 (m, 3H), 3.19 (ddd, J=14.8, 8.8, 6.1 Hz, 1H), 3.34 (ddd,J=14.5, 9.8, 5.5 Hz, 1H), 3.36 (ddd, J=14.5, 9.8, 5.5 Hz, 1H), 3.45(ddd, J=14.8, 9.0, 6.0 Hz, 1H), 3.73 (dd, J=11.5, 3.1 Hz, 1H), 3.95 (dd,J=11.6, 5.0 Hz, 1H), 6.25 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 6.79 (d,J=7.9 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.60 (dd, J=7.9, 2.3 Hz, 1H),8.24 (d, J=1.8 Hz, 1H); MS (DCI/NH₃) m/z 374.3 (M+H)⁺.

Example 1968-[2-(6-chloropyridin-3-yl)ethyl]-11-methyl-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

In a 50 mL round-bottom flask were combined2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (0.237 g, 0.905 mmol;Example 117D) and 1-azatricyclo[4.3.1.1^(3,8)]undecan-4-one (0.194 g,1.177 mmol; Example 190B) in dioxane (2 mL). After warming to 50° C. for10 minutes, the suspension cleared. Concentrated sulfuric acid (0.241mL, 4.53 mmol) was added and the mixture was heated at 80° C. After 1.5hours, the flask contained two phases. The mixture was cooled and theupper layer was decanted from the solid lower phase. The residue wasdissolved in water (75 mL), basified with concentrated sodium hydroxide(30 mmol), extracted with chloroform (4×25 mL), dried over magnesiumsulfate, and concentrated to give a crude solid. This material waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile inbuffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 withammonium hydroxide) over 15 minutes] to afford the title compound: ¹HNMR (300 MHz, methanol-d₄) δ ppm 1.62 (br d, J=13.2 Hz, 1H), 1.89 (br d,J=13.2 Hz, 1H), 1.89-1.93 (m, 1H), 2.12 (dt, J=12.9, 5.1 Hz, 1H), 2.24(ddd, J=13.7, 5.3, 5.1 Hz, 1H), 2.38 (s, 3H), 2.73 (t, J=4.9 Hz, 1H),2.76 (d, J=13.6 Hz, 1H), 2.94 (t, J=4.9 Hz, 1H), 3.04 (t, J=6.4 Hz, 2H),3.09 (d, J=13.6 Hz, 1H), 3.15-3.21 (m, 2H), 3.22 (dd, J=13.5, 4.7 Hz,1H), 3.38 (dd, J=13.4, 4.6 Hz, 1H), 4.34 (t, J=6.4 Hz, 1H), 4.35 (t,J=6.4 Hz, 1H), 6.86 (dd, J=8.2, 1.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H),7.12 (br s, 1H), 7.25 (dd, J=8.1, 0.7 Hz, 1H), 7.34 (dd, J=8.1, 2.4 Hz,1H), 7.80 (d, J=2.0 Hz, 1H); MS (DCI/NH₃) m/z 392.3 (M+H)⁺.

Example 19711-methyl-8-[2-(2-methylphenyl)ethyl]-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole

Sodium dispersion in paraffin (30%, 75 mg, 0.98 mmol) was combined with11-methyl-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole(120 mg, 0.48 mmol; Example 192) in a 20 mL vial with stir bar andseptum cap. Dimethyl sulfoxide (2.0 mL) was added, and the vial wasevacuated and purged with nitrogen (10 cycles). The mixture was stirredat room temperature for 30 minutes, and a solution of 2-methylstyrene(116 mg, 0.97 mmol; Aldrich) and hydroquinone (16 mg, 0.15 mmol;Aldrich) in dimethyl sulfoxide (0.5 mL) was added. The vial wasevacuated and purged with nitrogen (5 cycles) and the mixture wasstirred with heating at 105° C. for 114 hours. The resulting mixture wascooled to room temperature, applied directly to a column of silica geland eluted with chloroform, then CHCl₃—CH₃OH-14.8 M aqueous NH₄OH(90:10:1). The product-containing fractions were combined andconcentrated under vacuum and the residue was further purified byreverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 40 mL/minute, 20-90% gradient of acetonitrile in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 20 minutes] to provide the free base of the title compound. Thismaterial was dissolved in ethyl acetate (3 mL) and ethanol (0.5 mL) anda solution of HCl in dioxane (4 M; 0.1 mL; Aldrich) was added. The palesolution was stirred at room temperature for 2 hours, then concentratedunder vacuum to leave a solid. This was triturated with ethyl acetate (4mL) and dried under vacuum to provide the title compound as the HClsalt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.48 (d, J=13.9 Hz, 1H), 1.84(d, J=13.6 Hz, 1H), 1.95 (s, 3H), 1.97-2.05 (m, 1H), 2.18-2.41 (m, 3H),2.42 (s, 3H), 2.98 (t, J=4.9 Hz, 1H), 3.04-3.14 (m, 2H), 3.16-3.25 (m,1H), 3.32-3.39 (m, 1H), 3.39-3.57 (m, 3H), 3.73 (dd, J=12.6, 4.8 Hz,1H), 4.30-4.53 (m, 2H), 6.74 (d, J=7.1 Hz, 1H), 6.96-7.04 (m, 2H), 7.07(d, J=3.7 Hz, 1H), 7.07 (s, 1H), 7.22 (s, 1H), 7.32 (d, J=8.5 Hz, 1H);MS (DCI) m/z 371 (M+H)⁺.

Example 1985-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indoleExample 198A 8-methyl-8-azabicyclo[3.2.1]octan-6-one

A suspension of exo-6-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane (1.95g, 13.8 mmol; J. Heterocycl. Chem. 1968, 5, 423) and 2-iodoxybenzoicacid (4.83 g, 17.2 mmol; Aldrich) in ethyl acetate (90 mL) was heated at80° C. for 2.2 hours. The liquid phase was cooled and decanted. Theremaining residue was heated briefly at 80° C. with additional ethylacetate (30 mL), then cooled before the liquid phase was removed. Thecombined solutions were cooled to 10° C. and filtered. The filtrate waspartially concentrated, allowed to stand overnight, filtered again,concentrated and purified by flash chromatography (silica,acetonitrile/ethyl acetate then 2% 14.8 M aqueous ammonium hydroxide inacetonitrile) to afford the title compound: MS (DCI/NH₃) m/z 140 (M+H)⁺.

Example 198B5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole

A suspension of 2-chloro-5-(2-(1-p-tolylhydrazinyl)ethyl)pyridine (393mg, 1.5 mmol; Example 117D), 8-methyl-8-azabicyclo[3.2.1]octan-6-one(283 mg, 2.0 mmol; Example 198A), and KHSO₄ (272 mg, 2.0 mmol) indioxane (5 mL) was heated at 50° C. for 60 minutes. More dioxane (2 mL)was added, and the suspension was heated at 75° C. for 100 minutes.Concentrated sulfuric acid (0.25 mL) was added and heating was continuedovernight. After cooling the reaction mixture to room temperature, thedioxane phase was removed and the gummy residue was dissolved inmethanol and added to concentrated aqueous ammonium hydroxide (5 mL).The mixture was extracted with ethyl acetate (3×), and the combinedorganic phases were concentrated. This was extracted back into ethylacetate, and the extracts were dried (sodium sulfate), concentrated, andpurified by flash chromatography (silica, 0-100% gradient ofacetonitrile-ethyl acetate, then 2% 14.8 M aqueous ammonium hydroxide inacetonitrile) to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 0.15-0.36 (m, 1H), 1.13-1.33 (m, 2H), 1.41-1.53 (m,1H), 1.68-1.89 (m, 2H), 2.20 (s, 3H), 2.40 (s, 3H), 3.07-3.22 (m, 2H),3.56 (dd, J=2.7, 2.7 Hz, 1H), 3.92 (dd, J=2.7, 2.7 Hz, 1H), 4.20 (ddd,J=14.4, 8.4, 8.4 Hz, 1H), 4.48 (ddd, J=14.4, 5.7, 5.7 Hz, 1H), 6.95 (dd,J=8.5, 1.6 Hz, 1H), 7.12-7.19 (m, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.27 (d,J=8.2 Hz, 1H), 7.47 (dd, J=8.2, 2.4 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H); MS(ESI) m/z 366 (M+H)⁺.

Example 199(6R,10S)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole

The individual enantiomers of the racemic mixture of Example 198B wereseparated by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 20% CH₃OH—CO₂containing 0.1% diethylamine, flow rate 40 mL/minute) to afford thetitle compound as the first-eluting enantiomer (retention time 10.01minutes).

Example 200(6S,10R)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole

The individual enantiomers of the racemic mixture of Example 198B wereseparated by preparative chiral supercritical fluid chromatography(ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 20% CH₃OH—CO₂containing 0.1% diethylamine, flow rate 40 mL/minute) to afford thetitle compound as the second-eluting enantiomer (retention time 11.61minutes).

Example 20110-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole Example201A ethyl 1-(3-ethoxy-3-oxopropyl)piperidine-3-carboxylate

A 25 mL round-bottom flask was charged with ethyl nipecotate (4.0 mL,25.7 mmol, Aldrich) and ethyl acrylate (3.4 mL, 31.4 mmol; Aldrich). Theflask was purged with nitrogen and the mixture was heated to 80° C. for20 hours, then purified by silica gel chromatography (ethylacetate-dichloromethane-triethylamine 50:50:1; Rf=0.28) to afford thetitle compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.23-1.28 (m, 6H),1.42-1.59 (m, 2H), 1.68-1.74 (m, 1H), 1.89-1.95 (m, 1H), 2.01-2.08 (m,1H), 2.17-2.24 (m, 1H), 2.46-2.56 (m, 3H), 2.68-2.76 (m, 3H), 2.94-2.99(m, 1H), 4.09-4.17 (m, 4H); MS (DCI/NH₃) m/z 258 (M+H)⁺.

Example 201B 1-azabicyclo[3.3.1]nonan-4-one

A suspension of potassium tert-butoxide (8.15 g, 72.6 mmol; Aldrich) intoluene (200 mL) was heated to reflux for 15 minutes, then a solution ofethyl 1-(3-ethoxy-3-oxopropyl)-piperidine-3-carboxylate (6.16 g, 23.9mmol) in toluene (50 mL) was added dropwise over 1 hour to the refluxingreaction mixture. After the addition was complete, the reaction washeated to reflux for an additional 5 hours, cooled to ambienttemperature, and extracted with water (3×50 mL). The combined aqueouslayers were acidified with concentrated hydrochloric acid (40 mL), thenheated to reflux for 22 hours. The reaction was basified with 45 weight% potassium hydroxide (˜35 mL) and extracted with chloroform (3×100 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to afford the title compound: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.50-1.81 (m, 2H), 1.90-1.96 (m, 2H), 2.39-2.43 (m, 1H),2.49-2.54 (m, 2H), 3.08-3.41 (m, 6H); MS (DCI/NH₃) m/z 140 (M+H)⁺.

Example 201C10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole

A solution of 1-azabicyclo[3.3.1]nonan-4-one (2.05 g, 14.73 mmol;Example 201B) and p-tolylhydrazine hydrochloride (2.46 g, 15.51 mmol;Aldrich) in ethanol (50 mL) was treated with 4 M HCl in dioxane (4 mL,16 mmol; Aldrich) and the reaction mixture was heated to reflux for 16hours. The reaction was allowed to cool to ambient temperature affordinga precipitate that was isolated by filtration and washed with additionalethanol (10×2 mL) to provide a solid (3.03 g). This material wasdissolved in 1 M aqueous NaOH (50 mL) and extracted with chloroform(3×50 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to afford the title compound: ¹H NMR(300 MHz, CDCl₃) δ ppm 1.23-1.28 (m, 1H), 1.40-1.53 (m, 1H), 1.79-1.98(m, 2 H), 2.39 (s, 3H), 2.89 (br s, 1H), 2.99-3.10 (m, 3H), 3.20-3.24(m, 1H), 3.87 (d, J=16.3 Hz, 1H), 4.32 (d, J=16.3 Hz, 1H), 6.88 (dd,J=8.1, 1.4 Hz, 1H), 7.14-7.18 (m, 2H); MS (DCI/NH₃) m/z 227 (M+H)⁺.Anal. Calcd. for C₁₅H₁₈N₂.0.1H₂O: C, 78.98; H, 8.04; N, 12.28. Found: C,78.98; H, 8.04; N, 12.28.

Example 20210-methyl-7-[2-(6-methylpyridin-3-yl)ethyl]-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole

A solution of10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (173.8mg, 0.768 mmol; Example 201) in dimethyl sulfoxide (3 mL) was treatedwith sodium (30% dispersion in paraffin; 87.7 mg, 1.144 mmol; Aldrich),2-methyl-5-vinylpyridine (204.6 mg, 1.717 mmol; prepared as described inInternational Publication No. WO 2001017968) and hydroquinone (28.6 mg,0.260 mmol; Aldrich). The reaction was purged with nitrogen for 15minutes, then heated to 100° C. for 17 hours. After cooling, thereaction was partitioned between 1 M aqueous K₂CO₃ (35 mL) andchloroform (3×35 mL). The combined organic layers were washed with brine(35 mL), dried over sodium sulfate, filtered and concentrated. Methanol(10 mL) was added to the residue and the resulting suspension wasfiltered through diatomaceous earth, then purified by preparative HPLC(Phenomenex® Luna® Combi-HTS™ C8(2) 5 μm 100 Å AXIA™ 30×75 mm column,gradient of 10-100% acetonitrile in 0.1% trifluoroacetic acid, flow rate50 mL/minute) to afford the title compound as the bis trifluoroaceticacid salt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.54-1.78 (m, 3H),1.95-2.05 (m, 1H), 2.41 (s, 3H), 2.67 (s, 3H), 3.42-3.55 (m, 4H),3.68-3.72 (m, 1H), 4.34-4.41 (m, 1H), 4.48-4.57 (m, 2H), 7.01 (d, J=8.3Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.27 (s, 1H), 7.69 (d, J=8.3 Hz, 1H),8.03 (dd, J=8.3, 2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H); MS (DCI/NH₃) m/z347 (M+H)⁺.

Example 20310-methyl-7-[2-(2-methylphenyl)ethyl]-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole

The coupling of10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (226.0mg, 0.999 mmol; Example 201) and 2-methylstyrene (209.0 mg, 176.9 mmol,Alfa Aesar) was performed as described in Example 202, except that thematerial was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μmOBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofacetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted topH 10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.09-1.17 (m, 1H),1.29-1.47 (m, 2H), 1.65-1.74 (m, 1H), 1.97 (s, 3H), 2.18-2.24 (m, 1H),2.42 (s, 3H), 2.60-2.65 (m, 1H), 2.94-3.08 (m, 5H), 3.81 (d, J=16.3 Hz,1H), 4.05-4.15 (m, 1H), 4.23 (d, J=16.3 Hz, 1H), 4.36-4.45 (m, 1H), 6.78(d, J=7.1 Hz, 1H), 6.95-7.06 (m, 4H), 7.16-7.18 (m, 1H), 7.27 (d, J=8.1Hz, 1H); MS (DCI/NH₃) m/z 345 (M+H)⁺.

Example 2047-[2-(4-chlorophenyl)ethyl]-10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole

The coupling of10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (245.1mg, 1.083 mmol; Example 201) and 4-chlorostyrene (256.3 mg, 1.709 mmol,Aldrich) was performed as described in Example 202, except that thematerial was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μmOBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofacetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted topH 10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.13-1.45 (m, 3H),1.67-1.79 (m, 1H), 2.31-2.35 (m, 1H), 2.42 (s, 3H), 2.63-2.69 (m, 1H),2.96-3.11 (m, 5H), 3.82 (d, J=16.3 Hz, 1H), 4.07-4.15 (m, 1H), 4.24 (d,J=16.3 Hz, 1H), 4.34-4.42 (m, 1H), 6.78-6.83 (m, 2H), 6.97-7.00 (m, 1H),7.12-7.19 (m, 3H), 7.27-7.31 (m, 1H); MS (DCI/NH₃) m/z 365 (M+H)⁺.

Example 2055-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indoleExample 205A 2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

A mixture of 2-iodoaniline (1.00 g, 4.57 mmol; Aldrich),quinuclidin-3-one hydrochloride (1.24 g, 7.67 mmol; Aldrich),palladium(II) acetate (51 mg, 0.23 mmol; Aldrich),1,4-diazabicyclo[2.2.2]octane (DABCO; 1.79 g, 15.98 mmol; Aldrich) andmagnesium sulfate (0.88 g, 7.31 mmol; Aldrich) in dryN,N-dimethylformamide (14 mL) was evacuated and purged with nitrogen(three cycles) and stirred at 110° C. for 18 hours. The reaction mixturewas cooled to ambient temperature and filtered through a microfiberfrit. The filtrate was concentrated in vacuo, dissolved in methanol (10mL) and purified by preparative HPLC [Waters XBridge™ RP18 column, 5 μm,30×100 mm, flow rate 40 mL/minute, 10-99% gradient of methanol in buffer(0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammoniumhydroxide)] to afford the title compound: ¹H NMR (500 MHz, methanol-d₄)δ ppm 1.52-1.66 (m, 2H), 1.97-2.06 (m, 2H), 2.58-2.71 (m, 2H), 3.24-3.31(m, 2H), 3.40-3.45 (quintet, J=2.9 Hz, 1H), 6.94-7.05 (m, 2H), 7.31-7.35(m, 1H), 7.52-7.57 (m, 1H); MS (APCI) m/z 199 (M+H)⁺.

Example 205B5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

The coupling of 2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (110mg, 0.56 mmol; Example 205A) and 2-methyl-5-vinylpyridine (99 mg, 0.83mmol; prepared as described in International Publication No. WO2001017968) was performed according to the procedure described inExample 106A to provide the title compound: ¹H NMR (500 MHz,methanol-d₄) δ ppm 0.91-1.05 (m, 2H), 1.75-1.85 (m, 2H), 2.38 (s, 3H),2.42-2.51 (m, 2H), 3.09-3.21 (m, 5H), 4.44-4.50 (m, 2H), 7.02-7.12 (m,3H), 7.27 (dd, J=7.9, 2.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.56 (d,J=7.3 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H); MS (ESI) m/z 476 (M+H)⁺.

Example 206(4aR*,9bR*)-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1,4-ethanopyrido[3,2-b]indole

A solution of5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole(45 mg, 0.14 mmol; Example 205B) in trifluoroacetic acid (1.0 mL) wascooled to −30° C. and a solution of sodium cyanoborohydride (66 mg, 0.99mmol) in methanol (0.5 mL) was added dropwise over a period of 30minutes. The reaction mixture was allowed to slowly warm up to ambienttemperature over a period of 30 minutes. The mixture was concentrated onthe rotavap and then twice azeotroped with methanol (30 mL). The residuewas purified by preparative HPLC (Waters XBridge™ RP18 column, 5 μm,30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in 0.1%aqueous trifluoroacetic acid) to afford the title compound as thetrifluoroacetic acid salt: ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.75-1.86(m, 1H), 1.96-2.10 (m, 2H), 2.14-2.25 (m, 1H), 2.48-2.54 (m, 1H), 2.74(s, 3H), 2.86-2.95 (m, 1H), 3.04-3.15 (m, 3H), 3.42-3.57 (m, 3H), 3.71(dt, J=15.3, 7.6 Hz, 1H), 4.21 (dd, J=10.4, 4.3 Hz, 1H), 5.21 (d, J=10.4Hz, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.74 (t, J=7.5 Hz, 1H), 7.22-7.30 (m,2H), 7.82 (d, J=8.2 Hz, 1H), 8.44 (dd, J=8.2, 2.1 Hz, 1H), 8.65 (d,J=1.5 Hz, 1H); MS (ESI) m/z 320 (M+H)⁺.

Example 2075-[2-(2-methylphenyl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

The coupling of 2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (30 mg,0.15 mmol; Example 205A) and 2-methylstyrene (27 mg, 0.23 mmol; Aldrich)was performed according to the procedure described in Example 106Aexcept that the product was purified by reverse-phase HPLC (WatersXBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99%gradient of methanol in 0.1% aqueous trifluoroacetic acid) to afford thetitle compound as a trifluoroacetic acid salt: ¹H NMR (500 MHz,methanol-d₄) δ ppm 1.03-1.12 (m, 2H), 1.93-2.00 (m, 2H), 2.01 (s, 3H),2.90-2.99 (m, 2H), 3.16-3.22 (m, 2H), 3.33 (quintet, J=3.1 Hz, 1H), 3.70(ddd, J=11.1, 9.5, 4.4 Hz, 2H), 4.57-4.64 (m, 2H), 6.67 (d, J=7.6 Hz,1H), 6.95 (td, J=7.2, 1.7 Hz, 1H), 7.02-7.09 (m, 2H), 7.20-7.26 (m, 1H),7.29-7.34 (m, 1H), 7.61-7.69 (m, 2H); MS (APCI) m/z 317 (M+H)⁺.

Example 208 7-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

2-Iodo-5-methylaniline (1.0 g, 4.29 mmol; Amfinecom), quinuclidin-3-onehydrochloride (1.24 g, 7.67 mmol; Aldrich), palladium(II) acetate (48mg, 0.22 mmol; Aldrich), 1,4-diazabicyclo[2.2.2]octane (DABCO; 1.73 g,15.4 mmol; Aldrich) and magnesium sulfate (0.88 g, 7.31 mmol) wereprocessed as described in Example 205A to provide the title compound: ¹HNMR (500 MHz, methanol-d₄) δ ppm 1.52-1.63 (m, 2H), 1.94-2.05 (m, 2H),2.40 (s, 3H), 2.59-2.71 (m, 2H), 3.26 (ddd, J=12.2, 8.5, 4.3 Hz, 2H),3.40 (quintet, J=2.9 Hz, 1H), 6.85 (d, J=7.3, 0.7 Hz, 1H), 7.14 (s, 1H),7.42 (d, J=7.9 Hz, 1H); MS (DCI) m/z 213 (M+H)⁺.

Example 2097-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

The coupling of7-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (110 mg, 0.52mmol; Example 217) and 2-methyl-5-vinylpyridine (93 mg, 0.78 mmol;prepared as described in International Publication No. WO 2001017968)was performed according to the procedure described in Example 106A toprovide the title compound: ¹H NMR (500 MHz, methanol-d₄) δ ppm0.88-1.03 (m, 2H), 1.71-1.82 (m, 2H), 2.38 (s, 3H), 2.41-2.48 (m, 2H),2.44 (s, 3H), 3.07-3.17 (m, 5H), 4.42 (t, J=6.3 Hz, 2H), 6.89 (d, J=8.2Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 7.16 (s, 1H), 7.25 (dd, J=7.9, 2.1 Hz,1H), 7.44 (d, J=7.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H); MS (DCI) m/z 332(M+H)⁺.

Example 210(4aR*,9bR*)-7-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1,4-ethanopyrido[3,2-b]indole

The product of Example 209 (33 mg, 0.10 mmol) was processed as describedin Example 206 except that the product was purified by reverse-phaseHPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.30-1.41 (m, 1H),1.58-1.69 (m, 2H), 1.76-1.87 (m, 1H), 2.00-2.05 (m, 1H), 2.23 (s, 3H),2.48 (s, 3H), 2.49-2.57 (m, 1H), 2.59-2.67 (m, 1H), 2.80-2.92 (m, 2H),2.95-3.04 (m, 2H), 3.28-3.36 (m, 1H), 3.51 (ddd, J=14.6, 7.8, 6.6 Hz,1H), 3.62 (dd, J=10.1, 4.0 Hz, 1H), 4.42 (d, J=10.1 Hz, 1H), 6.16 (s,1H), 6.38 (d, J=7.3 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 7.21 (d, J=8.2 Hz,1H), 7.63 (dd, J=8.1, 2.3 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H); MS (APCI) m/z334 (M+H)⁺.

Example 211 8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

2-Iodo-4-methylaniline (2.0 g, 8.58 mmol; prepared as described in J.Org. Chem. 1999, 64, 9650), quinuclidin-3-one hydrochloride (2.36 g,14.6 mmol; Aldrich), palladium(II) acetate (145 mg, 0.646 mmol;Aldrich), 1,4-diazabicyclo[2.2.2]octane (DABCO; 3.47 g, 30.9 mmol;Aldrich) and magnesium sulfate (1.65 g, 13.7 mmol) were processed asdescribed in Example 205A to provide the title compound: ¹H NMR (500MHz, methanol-d₄) δ ppm 1.52-1.62 (m, 2H), 1.92-2.05 (m, 2H), 2.39 (s,3H), 2.55-2.69 (m, 2H), 3.22-3.29 (m, 2H), 3.40 (quintet, J=2.9 Hz, 1H),6.85 (dd, J=8.2, 1.5 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.34 (s, 1H); MS(APCI) m/z 213 (M+H)⁺.

Example 2128-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

The coupling of8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (80 mg, 0.38mmol; Example 211) and 2-methyl-5-vinylpyridine (85 mg, 0.71 mmol;prepared as described in International Publication No. WO 2001017968)was performed according to the procedure described in Example 106A toprovide the title compound: ¹H NMR (400 MHz, methanol-d₄) δ ppm0.87-1.08 (m, 2H), 1.64-1.87 (m, 2H), 2.39 (s, 3H), 2.41 (s, 3H),2.42-2.52 (m, 2H), 3.07-3.20 (m, 5H), 4.38-4.52 (m, 2H), 6.93 (dd,J=8.2, 1.2 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 7.26 (dd, J=5.8, 2.1 Hz,1H), 7.28 (d, J=8.5 Hz, 1H), 7.36 (s, 1H), 7.77 (d, J=2.1 Hz, 1H); MS(APCI) m/z 332 (M+H)⁺.

Example 213(4aR*,9bR*)-8-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1,4-ethanopyrido[3,2-b]indole

The product of Example 212 (27 mg, 0.08 mmol) was processed as describedin Example 206 except that the product was purified by reverse-phaseHPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (500 MHz, methanol-d₄) δ ppm 1.26-1.41 (m, 1H),1.59-1.72 (m, 2H), 1.77-1.89 (m, 1H), 2.00-2.07 (m, 1H), 2.19 (s, 3H),2.48 (s, 3H), 2.50-2.69 (m, 2H), 2.78-2.93 (m, 2H), 2.99-3.05 (m, 2H),3.29-3.37 (m, 1H), 3.48 (ddd, J=14.6, 8.2, 6.4 Hz, 1H), 3.61 (dd, J=9.9,3.8 Hz, 1H), 4.47 (d, J=10.1 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.91 (d,J=8.2 Hz, 1H), 6.96 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.63 (dd, J=7.9,2.4 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H); MS (APCI) m/z 334 (M+H)⁺.

Example 2148-methyl-5-[2-(2-methylphenyl)ethyl]-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

The coupling of8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (80 mg, 0.38mmol; Example 211) and 2-methylstyrene (85 mg, 0.72 mmol; Aldrich) wasperformed according to the procedure described in Example 106A toprovide the title compound: ¹H NMR (500 MHz, methanol-d₄) δ ppm0.87-1.03 (m, 2H), 1.60-1.76 (m, 2H), 1.97 (s, 3H), 2.38-2.46 (m, 2H),2.41 (s, 3H), 3.01 (quintet, J=2.9 Hz, 1H), 3.06-3.16 (m, 4H), 4.14-4.55(m, 2H), 6.77 (d, J=7.3 Hz, 1H), 6.91-6.97 (m, 2H), 6.99-7.03 (m, 2H),7.32 (d, J=8.2 Hz, 1H), 7.35 (s, 1H); MS (APCI) m/z 331 (M+H)⁺.

Example 2155-[(4-chlorophenyl)sulfonyl]-8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole

The coupling of8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (20 mg, 0.09mmol; Example 211) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14mmol; Aldrich) was performed according to the procedure described inExample 69, except that the product was purified by reverse-phase HPLC[Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute,20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.42-1.60 (m, 2H),1.92-2.13 (m, 2H), 2.40 (s, 3H), 2.45-2.61 (m, 2H), 3.13-3.27 (m, 2H),4.08 (quintet, J=2.9 Hz, 1H), 7.14 (dd, J=8.6, 1.5 Hz, 1H), 7.35 (s,1H), 7.46-7.55 (m, 2H), 7.76-7.87 (m, 2H), 8.01 (d, J=8.5 Hz, 1H); MS(ESI) m/z 387 (M+H)⁺.

Example 2166-isoquinolin-7-yl-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg,1.0 mmol; Example 2B) and 7-bromoisoquinoline (312 mg, 1.5 mmol;Frontier) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.20 (m, 4H) 2.42 (s,3H) 2.91-2.98 (m, 1H) 3.08-3.29 (m, 4H) 4.32 (s, 2H) 6.90-6.96 (m, 1H)6.98-7.04 (m, 1H) 7.22 (s, 1H) 7.73 (dd, J=8, 2 Hz, 1H) 7.94 (d, J=6 Hz,1H) 8.09 (d, J=2 Hz, 1H) 8.15 (d, J=9 Hz, 1H) 8.53 (d, J=6 Hz, 1H) 9.33(s, 1H); MS (DCI/NH₃) m/z 354 (M+H)⁺.

Example 2179-methyl-6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg,0.6 mmol; Example 2B) and 6-bromoquinoline (187 mg, 0.9 mmol; TCI-US)was performed as described in Example 68 to afford the title compound:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.95-2.20 (m, 4H) 2.42 (s, 3H)2.92-2.99 (m, 1H) 3.08-3.28 (m, 4H) 4.32 (s, 2H) 6.90-6.96 (m, 1H)6.98-7.04 (m, 1H) 7.22 (s, 1H) 7.63 (dd, J=8, 4 Hz, 1H) 7.72 (dd, J=9, 2Hz, 1H) 7.93 (d, J=2 Hz, 1H) 8.21 (d, J=9 Hz, 1H) 8.46 (d, J=7 Hz, 1H)8.94 (dd, J=4, 2 Hz, 1H); MS (DCI/NH₃) m/z 354 (M+H)⁺.

Example 2189-methyl-6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg,0.6 mmol; Example 2B) and 6-bromo-2-methylquinoline (200 mg, 0.9 mmol;Oakwood) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.19 (m, 4H) 2.41 (s,3H) 2.77 (s, 3H) 2.91-2.98 (m, 1H) 3.08-3.29 (m, 4H) 4.32 (s, 2H)6.89-6.94 (m, 1H) 6.96-7.01 (m, 1H) 7.21 (s, 1H) 7.52 (d, J=8 Hz, 1H)7.66 (dd, J=9, 2 Hz, 1H) 7.87 (d, J=2 Hz, 1H) 8.12 (d, J=9 Hz, 1H) 8.32(d, J=9 Hz, 1H); MS (DCI/NH₃) m/z 368 (M+H)⁺.

Example 2199-methyl-6-quinazolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg,0.6 mmol; Example 2B) and 6-bromoquinazoline (188 mg, 0.9 mmol; ParkwayScientific) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.22 (m, 4H) 2.42 (s,3H) 2.91-3.01 (m, 1H) 3.06-3.32 (m, 4H) 4.33 (s, 2H) 6.92-6.99 (m, 1H)7.02-7.09 (m, 1H) 7.23 (s, 1H) 7.99 (dd, J=9, 2 Hz, 1H) 8.12 (d, J=2 Hz,1H) 8.22 (d, J=9 Hz, 1H) 9.33 (s, 1H) 9.63 (s, 1H); MS (DCI/NH₃) m/z 355(M+H)⁺.

Example 2206-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg,0.6 mmol; Example 2B) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9mmol; ChemBridge) was performed as described in Example 68 to afford thetitle compound as the major product: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.95-2.21 (m, 4H) 2.42 (s, 3H) 2.90-2.97 (m, 1H) 3.09-3.41 (m, 4H) 4.33(s, 2H) 6.91-6.96 (m, 1H) 6.98-7.03 (m, 1H) 7.21 (s, 1H) 7.74-7.81 (m,1H) 7.86-7.93 (m, 1H) 8.11 (d, J=3 Hz, 1H) 8.17 (s, 1H); MS (DCI/NH₃)m/z 371 (M+H)⁺.

Example 2216-(4-methoxyquinazolin-6-yl)-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg,0.6 mmol; Example 2B) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9mmol; ChemBridge) was performed as described in Example 68 to afford thetitle compound as the minor product: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.95-2.20 (m, 4H) 2.42 (s, 3H) 2.89-2.96 (m, 1H) 3.09-3.30 (m, 4H) 4.23(s, 3H) 4.33 (s, 2H) 6.91-7.04 (m, 2H) 7.22 (s, 1H) 7.87 (dd, J=9, 2 Hz,1H) 8.06-8.13 (m, 2H) 8.83 (s, 1H); MS (DCI/NH₃) m/z 385 (M+H)⁺.

Example 2229-methyl-6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg,1.0 mmol; Example 2B) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm)was performed as described in Example 68 to afford the title compound:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.97-2.11 (m, 2H) 2.18-2.30 (m, 2H)2.43 (s, 3H) 3.10-3.29 (m, 5H) 4.32 (s, 2H) 6.96-7.01 (m, 1H) 7.22 (s,1H) 7.35 (d, J=8 Hz, 1H) 7.57 (d, J=8 Hz, 1H) 7.62-7.69 (m, 1H) 7.82(ddd, J=8, 7, 1 Hz, 1H) 7.97-8.05 (m, 2H) 8.52 (d, J=8 Hz, 1H); MS(DCI/NH₃) m/z 354 (M+H)⁺.

Example 2239-fluoro-6-isoquinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (78 mg,0.34 mmol; Example 161) and 7-bromoisoquinoline (106 mg, 0.51 mmol;Frontier) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.22 (m, 4H)2.88-2.96 (m, 1H) 3.08-3.29 (m, 4H) 4.31 (s, 2H) 6.85 (td, J=9, 2 Hz,1H) 7.06 (dd, J=9, 4 Hz, 1H) 7.12 (dd, J=10, 2 Hz, 1H) 7.74 (dd, J=9, 2Hz, 1H) 7.96 (d, J=6 Hz, 1H) 8.13 (d, J=2 Hz, 1H) 8.17 (d, J=8 Hz, 1H)8.55 (d, J=6 Hz, 1H) 9.35 (s, 1H); MS (DCI/NH₃) m/z 358 (M+H)⁺.

Example 2249-fluoro-6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg,1.0 mmol; Example 161) and 2-bromoquinoline (312 mg, 1.5 mmol; AlfaAesar) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.98-2.11 (m, 2H)2.17-2.31 (m, 2H) 3.09-3.28 (m, 5H) 4.31 (s, 2H) 6.90 (td, J=9, 3 Hz,1H) 7.13 (dd, J=9, 2 Hz, 1H) 7.42 (dd, J=9, 4 Hz, 1H) 7.57 (d, J=8 Hz,1H) 7.67 (t, J=8 Hz, 1H) 7.79-7.87 (m, 1H) 7.98-8.08 (m, 2H) 8.55 (d,J=8 Hz, 1H); MS (DCI/NH₃) m/z 358 (M+H)⁺.

Example 2259-fluoro-6-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg,1.0 mmol; Example 161) and 2-bromo-6-(1H-pyrazol-1-yl)pyridine (336 mg,1.5 mmol; Maybridge) was performed as described in Example 68 to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.99-2.14 (m,2H) 2.15-2.30 (m, 2H) 3.09-3.29 (m, 5H) 4.29 (s, 2H) 6.52-6.57 (m, 1H)6.90 (td, J=9, 3 Hz, 1H) 7.11 (dd, J=9, 3 Hz, 1H) 7.37 (d, J=8 Hz, 1H)7.43 (dd, J=9, 4 Hz, 1H) 7.80 (s, 1H) 7.97 (d, J=8 Hz, 1H) 8.16 (t, J=8Hz, 1H) 8.50 (d, J=3 Hz, 1H); MS (DCI/NH₃) m/z 374 (M+H)⁺.

Example 2269-fluoro-6-quinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg,1.0 mmol; Example 161) and 7-bromoquinoline (312 mg, 1.5 mmol; ArkPharm) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.95-2.22 (m, 4H)2.96-3.03 (m, 1H) 3.09-3.29 (m, 4H) 4.32 (s, 2H) 6.86 (td, J=9, 2 Hz,1H) 7.07-7.17 (m, 2H) 7.58-7.67 (m, 2H) 7.97 (d, J=2 Hz, 1H) 8.18 (d,J=9 Hz, 1H) 8.50 (d, J=8 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH₃)m/z 358 (M+H)⁺.

Example 2279-fluoro-6-quinazolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg,1.0 mmol; Example 161) and 7-bromoquinoline (314 mg, 1.5 mmol; ParkwayScientific) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.95-2.22 (m, 4H)2.91-2.98 (m, 1H) 3.09-3.29 (m, 4H) 4.31 (s, 2H) 6.87 (td, J=9, 2 Hz,1H) 7.07-7.17 (m, 2H) 7.99 (dd, J=9, 2 Hz, 1H) 8.16 (d, J=2 Hz, 1H) 8.24(d, J=9 Hz, 1H) 9.34 (s, 1H) 9.64 (s, 1H); MS (DCI/NH₃) m/z 359 (M+H)⁺.

Example 2289-fluoro-6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg,1.0 mmol; Example 161) and 6-bromoquinoline (312 mg, 1.5 mmol; TCI-US)was performed as described in Example 68 to afford the title compound:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.23 (m, 4H) 2.90-2.97 (m, 1H)3.07-3.30 (m, 4H) 4.31 (s, 2H) 6.85 (td, J=9, 3 Hz, 1H) 7.06 (dd, J=9, 4Hz, 1H) 7.12 (dd, J=10, 2 Hz, 1H) 7.64 (dd, J=8, 4 Hz, 1H) 7.73 (dd,J=9, 2 Hz, 1H) 7.97 (d, J=2 Hz, 1H) 8.23 (d, J=9 Hz, 1H) 8.47 (d, J=8Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH₃) m/z 358 (M+H)⁺.

Example 2299-fluoro-6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg,1.0 mmol; Example 161) and 6-bromo-2-methylquinoline (333 mg, 1.5 mmol;Oakwood) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.20 (m, 4H) 2.78 (s,3H) 2.89-2.96 (m, 1H) 3.08-3.30 (m, 4H) 4.30 (s, 2H) 6.84 (td, J=9, 2Hz, 1H) 7.04 (dd, J=9, 4 Hz, 1H) 7.11 (dd, J=9, 3 Hz, 1H) 7.54 (d, J=9Hz, 1H) 7.67 (dd, J=9, 2 Hz, 1H) 7.90 (d, J=2 Hz, 1H) 8.14 (d, J=9 Hz,1H) 8.33 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 372 (M+H)⁺.

Example 2306-(4-methoxyquinazolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(127 mg, 0.6 mmol; Example 187A) and 6-bromo-4-methoxyquinazoline (215mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 toafford the title compound as the minor product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.95-2.21 (m, 4H) 2.90-2.97 (m, 1H) 3.09-3.30 (m, 4H)4.23 (s, 3H) 4.35 (s, 2H) 7.08-7.13 (m, 3H) 7.41-7.47 (m, 1H) 7.89 (dd,J=9, 2 Hz, 1H) 8.10 (d, J=9 Hz, 1H) 8.14 (d, J=2 Hz, 1H) 8.85 (s, 1H);MS (DCI/NH₃) m/z 371 (M+H)⁺.

Example 2316-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(127 mg, 0.6 mmol; Example 187A) and 6-bromo-4-methoxyquinazoline (215mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 toafford the title compound as the major product: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.96-2.20 (m, 4H) 2.90-2.97 (m, 1H) 3.08-3.29 (m, 4H)4.36 (s, 2H) 7.07-7.13 (m, 3H) 7.39-7.46 (m, 1H) 7.75-7.82 (m, 1H)7.87-7.94 (m, 1H) 8.13 (d, J=2 Hz, 1H) 8.18 (s, 1H); MS (DCI/NH₃) m/z357 (M+H)⁺.

Example 2326-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 6-bromo-2-methylquinoline (333 mg,1.5 mmol; Oakwood) was performed as described in Example 68 to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.94-2.20 (m,4H) 2.78 (s, 3H) 2.91-2.98 (m, 1H) 3.09-3.29 (m, 4H) 4.35 (s, 2H)7.06-7.11 (m, 3H) 7.39-7.45 (m, 1H) 7.53 (d, J=8 Hz, 1H) 7.67 (dd, J=9,2 Hz, 1H) 7.89 (d, J=2 Hz, 1H) 8.13 (d, J=9 Hz, 1H) 8.33 (d, J=8 Hz,1H); MS (DCI/NH₃) m/z 354 (M+H)⁺.

Example 2336-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 6-bromoquinoline (312 mg, 1.5 mmol;TCI-US) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.95-2.22 (m, 4H)2.94-2.99 (m, 1H) 3.09-3.28 (m, 4H) 4.36 (s, 2H) 7.06-7.13 (m, 3H)7.39-7.47 (m, 1H) 7.64 (dd, J=8, 4 Hz, 1H) 7.74 (dd, J=9, 2 Hz, 1H) 7.96(d, J=2 Hz, 1H) 8.23 (d, J=9 Hz, 1H) 8.47 (d, J=8 Hz, 1H) 8.95 (dd, J=4,2 Hz, 1H); MS (DCI/NH₃) m/z 340 (M+H)⁺.

Example 2346-quinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 7-bromoquinoline (312 mg, 1.5 mmol;Ark Pharm) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.96-2.23 (m, 4H)2.99-3.05 (m, 1H) 3.10-3.30 (m, 4H) 4.37 (s, 2H) 7.07-7.21 (m, 3H)7.40-7.49 (m, 1H) 7.59-7.69 (m, 2H) 7.97 (d, J=2 Hz, 1H) 8.17 (d, J=9Hz, 1H) 8.50 (d, J=7 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH₃) m/z340 (M+H)⁺.

Example 2356-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 2-bromoquinoline (312 mg, 1.5 mmol;Alfa Aesar) was performed as described in Example 68 to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.97-2.12 (m, 2H)2.19-2.32 (m, 2H) 3.11-3.29 (m, 5H) 4.36 (s, 2H) 7.11-7.19 (m, 2H)7.40-7.48 (m, 2H) 7.60 (d, J=9 Hz, 1H) 7.66 (t, J=8 Hz, 1H) 7.79-7.87(m, 1H) 8.03 (t, J=7 Hz, 2H) 8.55 (d, J=8 Hz, 1H); MS (DCI/NH₃) m/z 340(M+H)⁺.

Example 2366-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 2-bromo-6-(1H-pyrazol-1-yl)pyridine(336 mg, 1.5 mmol; Maybridge) was performed as described in Example 68to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.99-2.12 (m, 2H) 2.17-2.30 (m, 2H) 3.09-3.30 (m, 5H) 4.33 (s, 2H)6.52-6.57 (m, 1H) 7.09-7.19 (m, 2H) 7.36-7.50 (m, 3H) 7.79 (s, 1H) 7.96(d, J=7 Hz, 1H) 8.12-8.22 (m, 1H) 8.50 (d, J=2 Hz, 1H); MS (DCI/NH₃) m/z356 (M+H)⁺.

Example 2376-[4-(4-methylpiperazin-1-yl)phenyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and1-(4-bromophenyl)-4-methylpiperazine (255 mg, 1.0 mmol; Accela Chembio)was performed as described in Example 68 to afford the title compound:¹H NMR (300 MHz, methanol-d₄) δ ppm 1.92-2.11 (m, 4H) 2.37 (s, 3H)2.61-2.71 (m, 4H) 2.86-2.92 (m, 1H) 3.03-3.28 (m, 8H) 4.31 (s, 2H)6.95-7.06 (m, 3H) 7.10-7.21 (m, 4H) 7.32-7.40 (m, 1H); MS (DCI/NH₃) m/z387 (M+H)⁺.

Example 2382-[2-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)ethyl]pyridazin-3(2H)-oneExample 238A[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole-κN²](trihydrido)boron

To a stirred solution of KOH (0.030 g, 0.541 mmol) in dimethyl sulfoxide(2 mL) at 25° C. was added dropwise a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (120 mg, 0.492 mmol, Example 164A) in 1 mL dimethyl sulfoxide.The mixture was stirred for 30 minutes, cooled to 0° C., and then(2-bromoethoxy)(tert-butyl)dimethylsilane (0.105 mL, 0.492 mmol,Aldrich) was added dropwise. A gradual warmup to room temperature wasallowed with continued stirring for 6 hours. The reaction was quenchedin water and extracted with ethyl acetate (3×5 mL). The combined organicphases were dried over sodium sulfate and concentrated in vacuo. Theresulting residue was purified by flash chromatography over silica gel(40 g) eluting with 10-50% ethyl acetate-hexane, to give the titlecompound: MS (DCI/NH₃) m/z 389 (M+H-BH₃)⁺.

Example 238B2-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)ethanol

The product of Experiment 238A (0.14 g, 0.348 mmol) was treated with HClin acetone/water (3 N, acetone:water=3:1, 10 mL), and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated in vacuo to give the title compound as the hydrochloridesalt: MS (DCI/NH₃) m/z 275 (M+H)⁺.

Experiment 238C6-(2-bromoethyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

Dibromotriphenylphosphorane (0.187 g, 0.444 mmol, Aldrich) was stirredin dichloromethane (2.5 mL) at 0° C. A solution of the product ofExperiment 238B (0.12 g, 0.386 mmol) in dichloromethane (2 mL) wasadded, and the resulting mixture was stirred overnight at roomtemperature. After concentrating in vacuo, the crude product waspurified by flash chromatography over silica gel (24 g), eluting with50-100% ethyl acetate-hexane, then switching to 100-0% ethyl acetate:[10% methanol (+10% 14.8 M aqueous NH₄OH):dichloromethane] to yield thetitle compound: MS (DCI/NH₃) m/z 337, 339 (M+H)⁺.

Experiment 238D2-[2-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)ethyl]pyridazin-3(2H)-one

The product of Experiment 238C (0.06 g, 0.178 mmol) andpyridazin-3(2H)-one (0.017 g, 0.178 mmol, Aldrich) were stirred inN,N-dimethylformamide (2 mL) at room temperature. K₂CO₃ (0.037 g, 0.267mmol) was added and stirring was continued overnight. The reaction waspoured into water and extracted with ethyl acetate (3×3 mL). Thecombined extracts were washed with brine, dried (MgSO₄), concentrated invacuo, and the residue was purified by flash chromatography over silicagel (12 g), eluting with 0-5% methanol (+10% 14.8 M aqueous NH₄OH):dichloromethane to give the title compound: ¹H NMR (300 MHz, CDCl₃) δppm 2.23-2.43 (m, 4H) 3.33-3.43 (m, 2H) 3.45-3.50 (m, 1H) 3.67-3.78 (m,2H) 4.40-4.49 (m, 2H) 4.53 (t, J=6.4 Hz, 2H) 4.60 (s, 2H) 6.83 (d, J=9.5Hz, 1H) 6.88-7.00 (m, 2H) 7.12 (dd, J=9.5, 3.7 Hz, 1H) 7.21 (dd, J=9.0,4.1 Hz, 1H) 7.61-7.66 (m, 1H); MS (DCI/NH₃) m/z 353 (M+H)⁺.

Example 2391-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridin-2(1H)-oneExample 239A6-(4-iodophenyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

3,4,5,6-Tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (1.50 g, 7.07 mmol,Example 187A), 1,4-diiodobenzene (3.50 g, 10.6 mmol, Aldrich), copper(I) iodide (0.202 g, 0.150 mmol, Aldrich), and cesium acetate (2.71 g,14.13 mmol, Aldrich) were combined in dimethyl sulfoxide (25 mL). Thereaction vial was sealed and evacuated then back filled with dry N₂(3×). The reaction mixture was heated to 90° C. overnight. The reactionmixture was cooled to room temperature, and then 10% 14.8 M aqueousNH₄OH in H₂O (40 mL) was added. The aqueous layer was extracted withethyl acetate (2×25 mL). The combined organic layers were dried overMgSO₄, and then the solid was removed by filtration. Volatiles wereremoved in vacuo. The resulting material was purified by flashchromatography [40 g silica gel column, 5-100% gradient of 14.8 Maqueous NH₄OH-methanol-dichloromethane (2:20:78) in dichloromethane] toafford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.93-2.25 (m,4H) 3.02 (s, 1H) 3.16-3.37 (m, 2H) 3.38-3.62 (m, 2H) 4.53 (s, 2H) 7.06(d, J=8.81 Hz, 2H) 7.09-7.22 (m, 3H) 7.38-7.48 (m, 1H) 7.88 (d, J=8.81Hz, 2H); MS (ESI+) m/z 415 (M+H)⁺.

Example 239B1-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridin-2(1H)-one

The product from Example 239A (440 mg, 1.06 mmol), pyridin-2(1H)-one(152 mg, 1.59 mmol, Aldrich), copper (67.5 mg, 1.06 mmol, Aldrich),copper(I) iodide (303 mg, 1.59 mmol, Aldrich), and K₂CO₃ (440 mg, 3.19mmol) were combined in pyridine (15 mL). The vial was sealed thenevacuated and flushed with dry N₂ (2×). N,N′-Dimethyl-ethylenediamine(0.034 ml, 0.319 mmol, Aldrich) was added and the reaction mixture washeated to 117° C. for 72 hours. Volatiles were removed in vacuo. Theresidue was partitioned between CHCl₃ (25 mL) and 14.8 M NH₄OH (10 mL).The organic layer was dried over MgSO₄, and the solid was removed byfiltration. The reaction mixture was concentrated in vacuo, and theresidue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofacetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted topH 10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.82-2.15 (m, 4H) 2.96-3.08 (m,1H) 3.08-3.26 (m, 2H) 3.23-3.42 (m, 2H) 4.38 (s, 2H) 6.25-6.37 (m, 1H)6.71 (d, J=9.83 Hz, 1H) 7.10-7.18 (m, 2H) 7.18-7.24 (m, 1H) 7.40-7.51(m, 5H) 7.60 (s, 2H); MS (ESI+) m/z 382 (M+H)⁺.

Example 2409-fluoro-6-{[6-(2-methylpyrrolidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

2-Methylpyrrolidine (0.230 mL, 2.248 mmol; Aldrich) and sodium carbonate(238 mg, 2.248 mmol; Aldrich) were added to a solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(400 mg, 1.124 mmol; Example 164C) in dimethyl sulfoxide (3.0 mL). Thereaction mixture was heated to 130° C. overnight. Volatiles were removedin vacuo. The resulting residue was dissolved in CH₂Cl₂ (25 mL) and thenwashed with H₂O (25 mL). The organic layer was dried over MgSO₄. Solidwas removed by filtration and volatiles were removed under reducedpressure. The residue was purified by flash chromatography, SiO₂ VarianSF-25 12 g column, gradient (0 to 100% CH₂Cl₂/methanol/14.8 M aqueousNH₄OH 78:20:2 in CH₂Cl₂) over 20 minutes to give the title compound: ¹HNMR (300 MHz, CHCl₃) δ ppm 1.16 (d, J=6.10 Hz, 3H) 1.86-2.25 (m, 8H)3.19 (s, 4H) 3.48 (d, J=17.29 Hz, 3H) 3.97-4.15 (m, 1H) 4.47 (s, 2H)5.16 (s, 2H) 6.25 (d, J=8.82 Hz, 1H) 6.81-7.10 (m, 3H) 7.17-7.35 (m, 1H)7.88 (d, J=2.71 Hz, 1H); MS (ESI) m/z 405 (M+H)⁺.

Example 2419-fluoro-6-{[6-(piperidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

In a 2.5 mL microwave vial, a solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(20 mg, 1 equivalent, Example 164C) dissolved in N-methylpyrrolidine(0.25 mL) was added, followed by the addition of piperidine (0.6 mmol,51 mg, 10.5 equivalents) dissolved in N-methylpyrrolidine (2 mL), andK₂CO₃ as a solid (3 equivalents). The vial was capped and heated at 220°C. for 30 minutes. The reaction was checked by LC/MS and concentrated todryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanoland then purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm100 Å AXIA column (30 mm×75 mm) to provide the title compound as thetrifluoroacetic acid salt. A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient 10-100%A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A).Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). AnAgilent 1100 Series Purification system was used, consisting of thefollowing modules: Agilent 1100 Series LC/MSD SL mass spectrometer withAPI-electrospray source; two Agilent 1100 Series preparative pumps;Agilent 1100 Series isocratic pump; Agilent 1100 Series diode arraydetector with preparative (0.3 mm) flow cell; Agilent active-splitter,IFC-PAL fraction collector/auto sampler. The make-up pump for the massspectrometer used 3:1 CH₃OH/H₂O with 0.1% formic acid at a flow rate of1 mL/minute. Fraction collection was automatically triggered when theextracted ion chromatogram (EIC) for the target mass exceeded thethreshold specified in the method. The system was controlled usingAgilent Chemstation (Rev B. 10.03), Agilent A2Prep, and Leap FractPalsoftware, with custom Chemstation macros for data export. ¹H NMR (400MHz, pyridine-d₅) δ ppm 1.20-1.43 (m, 4H) 1.87-2.13 (m, 4H) 3.08-3.32(m, 2H) 3.35-3.63 (m, 7H) 3.64-3.77 (m, 2H) 4.82 (s, 2H) 5.31 (s, 2H)6.55-6.77 (m, 1H) 7.11-7.20 (m, 1H) 7.28 (t, J=7.78 Hz, 2H) 7.56 (d,J=8.85 Hz, 1H) 8.23 (s, 1H); MS (ESI) m/z 405 (M+H)⁺.

Example 2425-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-isopropyl-N-methylpyridin-2-amine

In a 2.5 mL microwave vial, a solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(20 mg, 1 equivalent, Example 164C) dissolved in N-methylpyrrolidine(0.25 mL) was added, followed by the addition of N-methylpropan-2-amine(0.6 mmol, 44 mg, 10.5 equivalents) dissolved in N-methylpyrrolidine (2mL), and K₂CO₃ as a solid (3 equivalents). The vial was capped andheated at 220° C. for 30 minutes. The reaction was checked by LC/MS andconcentrated to dryness. The residue was dissolved in 1:1 dimethylsulfoxide/methanol and then purified by preparative HPLC on a PhenomenexLuna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm) to provide the titlecompound as the trifluoroacetic acid salt. A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient10-100% A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient100-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol(1:1). An Agilent 1100 Series Purification system was used, consistingof the following modules: Agilent 1100 Series LC/MSD SL massspectrometer with API-electrospray source; two Agilent 1100 Seriespreparative pumps; Agilent 1100 Series isocratic pump; Agilent 1100Series diode array detector with preparative (0.3 mm) flow cell; Agilentactive-splitter, IFC-PAL fraction collector/autosampler. The make-uppump for the mass spectrometer used 3:1 CH₃OH:H₂O with 0.1% formic acidat a flow rate of 1 mL/minute. Fraction collection was automaticallytriggered when the extracted ion chromatogram (EIC) for the target massexceeded the threshold specified in the method. The system wascontrolled using Agilent Chemstation (Rev B. 10.03), Agilent A2Prep, andLeap FractPal software, with custom Chemstation macros for data export.¹H NMR (400 MHz, pyridine-d₅) δ ppm 1.04 (s, 6H) 1.84-2.18 (m, 4H) 2.50(s, 1H) 2.72-2.85 (m, 3H) 3.18-3.49 (m, 3H) 3.70 (d, J=42.42 Hz, 2H)4.82 (s, 2H) 5.31 (s, 2H) 6.55-6.77 (m, 1H) 7.11-7.20 (m, 1H) 7.28 (t,J=7.78 Hz, 2H) 7.56 (d, J=8.85 Hz, 1H) 8.23 (s, 1H); MS (ESI) m/z 393(M+H)⁺.

Example 243N-(1,3-dioxolan-2-ylmethyl)-5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-methylpyridin-2-amine

In a 2.5 mL microwave vial, a solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(20 mg, 1 equivalent, Example 164C) dissolved in N-methylpyrrolidine(0.25 mL) was added, followed by the addition of1-(1,3-dioxolan-2-yl)-N-methylmethanamine (0.6 mmol, 70 mg, 10.5equivalents) dissolved in N-methylpyrrolidine (2 mL), and potassiumK₂CO₃ as a solid (3 equivalents). The vial was capped and heated at 220°C. for 30 minutes. The reaction was checked by LC/MS and concentrated todryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanoland then purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm100 Å AXIA column (30 mm×75 mm) to provide the title compound as thetrifluoroacetic acid salt. A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient 10-100%A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A).Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). AnAgilent 1100 Series Purification system was used, consisting of thefollowing modules: Agilent 1100 Series LC/MSD SL mass spectrometer withAPI-electrospray source; two Agilent 1100 Series preparative pumps;Agilent 1100 Series isocratic pump; Agilent 1100 Series diode arraydetector with preparative (0.3 mm) flow cell; Agilent active-splitter,IFC-PAL fraction collector/auto sampler. The make-up pump for the massspectrometer used 3:1 methanol:H₂O with 0.1% formic acid at a flow rateof 1 mL/minute. Fraction collection was automatically triggered when theextracted ion chromatogram (EIC) for the target mass exceeded thethreshold specified in the method. The system was controlled usingAgilent Chemstation (Rev B.10.03), Agilent A2Prep, and Leap FractPalsoftware, with custom Chemstation macros for data export. ¹H NMR (400MHz, pyridine-d₅) δ ppm 2.50 (s, 1H) 2.74-3.05 (m, 5H) 3.10 (s, 3H)3.25-3.45 (m, 3H) 3.50-3.66 (m, 2H) 3.68-3.78 (m, 2H) 3.83-3.97 (m, 2H)4.73 (s, 2H) 5.31 (s, 2H) 6.55-6.77 (m, 1H) 7.11-7.20 (m, 1H) 7.28 (t,J=7.78 Hz, 2H) 7.56 (d, J=8.85 Hz, 1H) 8.23 (s, 1H); MS (ESI) m/z 437(M+H)⁺.

Example 2449-fluoro-6-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

In a 2.5 mL microwave vial, a solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(20 mg, 1 equivalent, Example 164C) dissolved in N-methylpyrrolidine(0.25 mL) was added, followed by the addition of pyrrolidine (0.6 mmol,42 mg, 10.5 equivalents) dissolved in N-methylpyrrolidine (2 mL), andK₂CO₃ as a solid (3 equivalents). The vial was capped and heated at 220°C. for 30 minutes. The reaction was checked by LC/MS and concentrated todryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanoland then purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm100 Å AXIA column (30 mm×75 mm) to provide the title compound as thetrifluoroacetic acid salt. A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient 10-100%A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A).Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). AnAgilent 1100 Series Purification system was used, consisting of thefollowing modules: Agilent 1100 Series LC/MSD SL mass spectrometer withAPI-electrospray source; two Agilent 1100 Series preparative pumps;Agilent 1100 Series isocratic pump; Agilent 1100 Series diode arraydetector with preparative (0.3 mm) flow cell; Agilent active-splitter,IFC-PAL fraction collector/auto sampler. The make-up pump for the massspectrometer used 3:1 CH₃OH:H₂O with 0.1% formic acid at a flow rate of1 mL/minute. Fraction collection was automatically triggered when theextracted ion chromatogram (EIC) for the target mass exceeded thethreshold specified in the method. The system was controlled usingAgilent Chemstation (Rev B. 10.03), Agilent A2Prep, and Leap FractPalsoftware, with custom Chemstation macros for data export. ¹H NMR (400MHz, pyridine-d₅) δ ppm 1.43-1.54 (m, 2H) 1.53-1.64 (m, 2H) 1.90-2.01(m, 2H) 2.01-2.15 (m, 2H) 3.29-3.51 (m, 7H) 3.63-3.76 (m, 2H) 4.73 (s,2H) 5.31 (s, 2H) 6.55-6.77 (m, 1H) 7.11-7.20 (m, 1H) 7.28 (t, J=7.78 Hz,2H) 7.56 (d, J=8.85 Hz, 1H) 8.23 (s, 1H); MS (ESI) m/z 391 (M+H)⁺.

Example 2455-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]-N-(2-methoxyethyl)-N-methylpyridin-2-amine

In a 2.5 mL microwave vial, a solution of6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(20 mg, 1 equivalent, Example 164C) dissolved in N-methylpyrrolidine(0.25 mL) was added, followed by the addition of2-methoxy-N-methylethanamine (0.6 mmol, 53 mg, 10.5 equivalents)dissolved in N-methylpyrrolidine (2 mL), and K₂CO₃ as a solid (3equivalents). The vial was capped and heated at 220° C. for 30 minutes.The reaction was checked by LC/MS and concentrated to dryness. Theresidue was dissolved in 1:1 dimethyl sulfoxide/methanol and thenpurified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIAcolumn (30 mm×75 mm) to provide the title compound as thetrifluoroacetic acid salt. A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient 10-100%A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A).Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). AnAgilent 1100 Series Purification system was used, consisting of thefollowing modules: Agilent 1100 Series LC/MSD SL mass spectrometer withAPI-electrospray source; two Agilent 1100 Series preparative pumps;Agilent 1100 Series isocratic pump; Agilent 1100 Series diode arraydetector with preparative (0.3 mm) flow cell; Agilent active-splitter,IFC-PAL fraction collector/auto sampler. The make-up pump for the massspectrometer used 3:1 CH₃OH:H₂O with 0.1% formic acid at a flow rate of1 mL/minute. Fraction collection was automatically triggered when theextracted ion chromatogram (EIC) for the target mass exceeded thethreshold specified in the method. The system was controlled usingAgilent Chemstation (Rev B.10.03), Agilent A2Prep, and Leap FractPalsoftware, with custom Chemstation macros for data export. ¹H NMR (400MHz, pyridine-d₅) δ ppm 1.86-2.07 (m, 4H) 3.04 (s, 3H) 3.21 (s, 3H)3.25-3.35 (m, 3H) 3.35-3.41 (m, 2H) 3.48-3.60 (m, 2H) 3.73-3.82 (m, 2H)4.73 (s, 2H) 5.31 (s, 2H) 6.55-6.77 (m, 1H) 7.11-7.20 (m, 1H) 7.28 (t,J=7.78 Hz, 2H) 7.56 (d, J=8.85 Hz, 1H) 8.23 (s, 1H); MS (ESI) m/z 409(M+H)⁺.

Example 2469-fluoro-6-[(5-fluoropyridin-3-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 246A 3-fluoro-5-{[1-(4-fluorophenyl)hydrazino]methyl}pyridine

Triethylamine (2.57 mL, 18.45 mmol) was added to a suspension of(4-fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) inethanol (12 mL), 3-(bromomethy)-5-fluoropyridine (701 mg, 3.69 mmol;Biogene Organics) was added to this solution. The reaction mixture washeated to 70° C. for 3 hours. Volatiles were removed in vacuo. Ethanol(5 mL) was added to dissolve the solid. 4 M Aqueous HCl (2 mL) was addedto make the solution acidic (pH 1). Volatiles were removed under invacuo. The resulting residue was carried on to the next step withoutfurther purification.

Example 246B9-fluoro-6-[(5-fluoropyridin-3-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The product from Example 246A (290 mg, 1.2 mmol) and1-azabicyclo[3.2.2]nonan-4-one (172 mg, 1.233 mmol, Example 2A) weredissolved in 7% sulfuric acid in dioxane (v/v, 10 mL). The reactionmixture was stirred at 80° C. for 24 hours. The reaction mixture wascooled to room temperature then made basic by the addition of 4 MNaOH_(aq). The aqueous layer was extracted with CH₂Cl₂. The organiclayer was dried over MgSO₄, and then solid was removed by filtration.The reaction mixture was concentrated in vacuo, and the residue waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanol in 0.1%trifluoracetic acid in water over 20 minutes] to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 2.00-2.18 (m, 2H) 2.24-2.41 (m, 2H) 3.40-3.58 (m, 3H) 3.57-3.71(m, 2H) 4.76 (s, 2H) 5.60 (s, 2H) 6.89-7.08 (m, 1H) 7.14-7.32 (m, 2H)7.44 (dd, J=8.98, 4.24 Hz, 1H) 8.07 (s, 1H) 8.38 (d, J=2.71 Hz, 1H); MS(DCI) m/z 340 (M+H)⁺.

Example 2479-fluoro-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 247A5-{[1-(4-fluorophenyl)hydrazino]methyl}-2-(1H-pyrazol-1-yl)pyridine

Triethylamine (2.57 mL, 18.45 mmol) was added to a suspension of(4-fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) inethanol (12 mL), 5-(chloromethyl)-2-(1H-pyrazol-1-yl)pyridine (715 mg,3.69 mmol; ABCHEM-Inc) was added to this solution. The reaction mixturewas heated to 70° C. for 3 hours. Volatiles were removed in vacuo.Ethanol (5 mL) was added to dissolve the solid. 4 M Aqueous HCl (2 mL)was added to make the solution acidic (pH 1). Volatiles were removed invacuo. The resulting residue was carried on to the next step withoutfurther purification.

Example 247B9-fluoro-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The product from Example 247A (290 mg, 1.02 mmol) and1-azabicyclo[3.2.2]nonan-4-one (142 mg, 1.02 mmol, Example 2A) weredissolved in 7% sulfuric acid in dioxane (v/v, 10 mL). The reactionmixture was stirred at 80° C. for 24 hours. The reaction mixture wascooled to room temperature then made basic by the addition of 4 MNaOH_(aq). The aqueous layer was extracted with CH₂Cl₂. The organiclayer was dried over MgSO₄ and then the solid was removed by filtration.The reaction mixture was concentrated in vacuo, and the residue waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanol in 0.1%trifluoracetic acid in water over 20 minutes] to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.84-2.04 (m, 2H) 2.04-2.24 (m, 2H) 3.10-3.28 (m, 2H) 3.32-3.46(m, 3H) 4.39 (s, 2H) 5.54 (s, 2H) 6.49 (s, 1H) 6.87-6.98 (m, 1H) 7.11(dd, J=9.49, 2.37 Hz, 1H) 7.41 (dd, J=8.98, 4.24 Hz, 1H) 7.50 (dd,J=8.82, 2.37 Hz, 1H) 7.72 (s, 1H) 7.83 (d, J=8.48 Hz, 1H) 8.09 (s, 1H)8.52 (d, J=3.05 Hz, 1H); MS (ESI) m/z 388 (M+H)⁺.

Example 2482-{5-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]pyridin-2-yl}pyridazin-3(2H)-one

A sealed tube was charged with6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(150 mg, 0.422 mmol, Example 164C), pyridazin-3(2H)-one (81 mg, 0.843mmol; Fluka), copper (26.8 mg, 0.422 mmol; Aldrich), copper (I) iodide(120 mg, 0.632 mmol; Aldrich), and pyridine (3.5 mL). The tube wasflushed with nitrogen (2×). N,N′-Dimethyl-ethylenediamine (0.014 mL,0.126 mmol) was added to the tube, and the mixture was heated to 117° C.for 72 hours. Volatiles were removed under reduced pressure. The residuewas partitioned between CHCl₃ and 14.8M NH₄OH_(aq). The organic layerwas dried over MgSO₄ and the solid was removed by filtration. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 20-95% gradient of methanol in 0.1%trifluoracetic acid in water over 20 minutes] to afford the titlecompound as the trifluoroacetic acid salt: ¹H NMR (300 MHz, CDCl₃) δ ppm2.03-2.19 (m, J=17.05, 17.05 Hz, 2H) 2.19-2.33 (m, 2H) 3.24-3.43 (m, 3H)3.57-3.74 (m, 2H) 4.65 (s, 2H) 5.41 (s, 2H) 6.94-7.12 (m, 3H) 7.16-7.42(m, 3H) 7.62-7.73 (m, 1H) 7.95 (s, 1H) 8.38 (s, 1H); MS (ESI) m/z 416(M+H)⁺.

Example 2499-fluoro-6-[(2-phenylpyrimidin-5-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (200 mg, 0.82 mmol, Example 164A) in tetrahydrofuran (10 mL) wasadded sodium hydride (60% dispersion in mineral oil; 47 mg, 1.18 mmol;Aldrich) in one portion. After stirring for 30 minutes,5-(chloromethyl)-2-phenylpyrimidine (168 mg, 0.819 mmol, AnichemProduct) was added, and the solution was heated to 60° C. overnight.After the solvent was removed, the residue was treated with HCl inacetone/water (3 N, acetone:water=3:1, 10 mL) and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated in vacuo, and the residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.82-2.05(m, 4H), 3.15 (m, 3H), 3.35 (m, 2H), 4.30 (s, 2H), 5.35 (s, 2H), 6.85(td, J=9, 3 Hz, 1H), 7.13 (dd, J=9, 1 Hz, 1H), 7.23 (dd, J=9, 2 Hz, 1H),7.42 (m, 4H), 8.40 (m, 3H); MS (ESI) m/z 399 (M+H)⁺.

Example 2506-(1H-benzimidazol-2-ylmethyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (200 mg, 0.82 mmol, Example 164A) in tetrahydrofuran (10 mL) wasadded sodium hydride (60% dispersion in mineral oil; 47 mg, 1.18 mmol;Aldrich) in one portion. After stirring for 30 minutes,2-(chloromethyl)-1H-benzo[d]imidazole (136 mg, 0.819 mmol, Aldrich) wasadded, and the solution was heated to 60° C. overnight. After thesolvent was removed, the residue was treated with HCl in acetone/water(3 N, acetone:water=3:1, 10 mL), and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated in vacuo,and the residue was purified by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.85-2.10 (m, 4H), 3.10-3.35 (m,5H), 4.35 (s, 2H), 5.25 (s, 2H), 6.85 (td, J=9, 3 Hz, 1H), 7.05 (m, 6H),11.05 (s, 1H); MS (ESI) m/z 361 (M+H)⁺.

Example 2519-fluoro-6-(quinolin-8-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (200 mg, 0.82 mmol, Example 164A) in tetrahydrofuran (10 mL) wasadded sodium hydride (60% dispersion in mineral oil; 47 mg, 1.18 mmol;Aldrich) in one portion. After stirring for 30 minutes,8-(bromomethyl)quinoline (182 mg, 0.819 mmol, Aldrich) was added and thesolution was heated to 60° C. overnight. After the solvent was removed,the residue was treated with HCl in acetone/water (3 N,acetone:water=3:1, 10 mL) and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated in vacuo,and the residue was purified by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.89-2.16 (m, 4H), 3.11-3.35 (m,3H), 3.35-3.56 (m, 2H), 4.50 (s, 2H), 6.03 (s, 2H), 6.67-6.76 (m, 1H),6.85-6.97 (m, 1H), 7.10 (dd, J=9.3, 2.2 Hz, 1H), 7.15-7.23 (m, 1H), 7.34(t, J=6.6 Hz, 1H), 7.52 (dd, J=8.1, 4.1 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H),8.22 (dd, J=8.1, 1.7 Hz, 1H), 9.00 (dd, J=4.4, 1.7 Hz, 1H); MS (ESI) m/z372 (M+H)⁺.

Example 2529-fluoro-6-[(3-methyl-1,2-oxazol-5-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (160 mg, 0.66 mmol, Example 164A) in tetrahydrofuran (10 mL) wasadded sodium hydride (60% dispersion in mineral oil; 37 mg, 0.98 mmol;Aldrich) in one portion. After stirring for 30 minutes,5-(bromomethyl)-3-methylisoxazole (121 mg, 0.66 mmol, Aldrich) wasadded, and the solution was heated to 60° C. overnight. After thesolvent was removed, the residue was treated with HCl in acetone/water(3 N, acetone:water=3:1, 10 mL), and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated in vacuo,and the residue was purified by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.92-2.13 (m, 4H), 2.21 (s, 3H),2.99-3.23 (m, 3H), 3.24-3.43 (m, 2H), 4.29 (s, 2H), 5.30 (s, 2H), 5.71(s, 1H), 6.87-6.98 (m, 1H), 7.04 (dd, J=9.3, 2.5 Hz, 1H), 7.17 (dd,J=8.8, 4.1 Hz, 1H); MS (DCI) m/z 326 (M+H)⁺.

Example 2536-[(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole N-boranecomplex (200 mg, 0.82 mmol, Example 164A) in tetrahydrofuran (10 mL) wasadded sodium hydride (60% dispersion in mineral oil; 47 mg, 1.18 mmol;Aldrich) in one portion. After stirring for 30 minutes,6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (166 mg, 0.819 mmol,Maybridge) was added, and the solution was heated to 60° C. overnight.After the solvent was removed, the residue was treated with HCl inacetone/water (3 N, acetone:water=3:1, 10 mL), and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated in vacuo, and the residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.13-2.41(m, 4H) 3.20-3.42 (m, 2H) 3.53-3.77 (m, 3H) 4.58 (s, 2H) 5.45 (s, 2H)6.95-7.05 (m, 2H) 7.07 (d, J=9.52 Hz, 1H) 7.32 (dd, J=8.73, 3.97 Hz, 1H)7.60 (s, 1H) 7.80 (d, J=9.52 Hz, 1H); MS (ESI) m/z 396 (M+H)⁺.

Example 2549-fluoro-6-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleExample 254A2-{[1-(4-fluorophenyl)hydrazino]methyl}imidazo[1,2-a]pyrimidine

Triethylamine (2.57 mL, 18.45 mmol) was added to a suspension of(4-fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) inethanol (12 mL), 2-(chloromethyl)imidazo[1,2-a]pyrimidine (715 mg, 3.69mmol; Anichem) was added to this solution. The reaction mixture washeated to 70° C. for 3 hours. Volatiles were removed in vacuo. Ethanol(5 mL) was added to dissolve the solid. 4 M Aqueous HCl (2 mL) was addedto make the solution acidic (pH 1). Volatiles were removed under reducedpressure. The resulting material was carried on to the next step withoutfurther purification.

Example 254B9-fluoro-6-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The product from Example 254A (290 mg, 1.02 mmol) and1-azabicyclo[3.2.2]nonan-4-one (157 mg, 1.13 mmol. Example 2A) weredissolved in 7% sulfuric acid in dioxane (v/v, 10 mL). The reactionmixture was stirred at 80° C. for 24 hours. The reaction mixture wascooled to room temperature and then made basic by the addition of 4 Maqueous NaOH. The aqueous layer was extracted with CH₂Cl₂. The organiclayer was dried over MgSO₄, and then the solid was removed byfiltration. The reaction mixture was concentrated in vacuo, and theresidue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of methanolin 0.1% trifluoracetic acid in water over 20 minutes] to afford thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 2.18-2.50 (m, 4H) 3.41-3.58 (m, 3H) 3.56-3.75 (m, 2H)4.68 (s, Hz, 2H) 5.60 (s, 2H) 6.85-7.17 (m, 3H) 7.48-7.54 (m, 2H) 8.54(d, J=6.44 Hz, 1H) 8.68-8.79 (m, 1H); MS (ESI) m/z 362 (M+H)⁺.

Example 2552-{4-[(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)methyl]phenyl}pyridazin-3(2H)-one

A sealed tube was charged with the product from Example 167B (350 mg,0.877 mmol), pyridazin-3(2H)-one (84 mg, 0.877 mmol; Fluka), copper (67mg, 1.05 mmol; Aldrich), copper (I) iodide (250 mg, 1.32 mmol; Aldrich)and pyridine (5.0 mL). The tube was flushed with nitrogen (2×).N,N′-Dimethyl-ethylenediamine (0.028 mL, 0.263 mmol) was added to thetube, and the reaction mixture was heated to 117° C. for 72 hours.Volatiles were removed under reduced pressure. The residue waspartitioned between CHCl₃ and 14.8 M aqueous NH₄OH. The organic layerwas dried over MgSO₄, and the solid was removed by filtration. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 20-95% gradient of methanol in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 20 minutes] to afford the title compound: ¹H NMR (300 MHz, CD3Cl) δppm 1.85-2.10 (m, 4H) 2.95-3.21 (m, 3H) 3.21-3.42 (m, 2H) 4.33 (s, 2H)5.35 (s, 2H) 6.84-6.94 (m, 1H) 7.00-7.09 (m, 4H) 7.13 (dd, J=8.92, 4.16Hz, 1H) 7.22 (t, J=3.57 Hz, 1H) 7.54 (d, J=8.33 Hz, 2H) 7.87 (dd,J=3.57, 1.59 Hz, 1H); MS (DCI) m/z 415 (M+H)⁺.

Example 2566-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (300 mg, 1.32 mmol, Example 187B) in tetrahydrofuran(15 mL) was added sodium hydride (60% dispersion in mineral oil; 66 mg,1.4 mmol; Aldrich) in one portion. After stirring for 30 minutes,5-(bromomethyl)-2-(trifluoromethyl)pyridine (318 mg, 1.32 mmol, AnichemProduct) was added, and the solution was heated to 60° C. overnight.After the solvent was removed, the residue was treated with HCl inacetone/water (3 N, acetone:water=3:1, 20 mL), and the mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, and the residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.80-1.90(m, 2H), 1.95-2.05 (m, 2H), 3.30-3.45 (m, 3H), 3.71 (m, 2H), 4.25 (s,2H), 5.45 (s, 2H), 7.05 (dd, J=8, 2 Hz, 1H), 7.25 (m, 1H), 7.33 (t, J=8Hz, 1H), 7.40 (dd, J=8, 2 Hz, 1H), 7.49 (dd, J=8, 2 Hz, 1H), 7.54 (d,J=8 Hz, 1H), 8.66 (s, 1H); MS (ESI) m/z 372 (M+H)⁺.

Example 2576-[(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

To a solution of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indoleN-borane complex (200 mg, 0.819 mmol, Example 187B) in tetrahydrofuran(15 mL) was added sodium hydride (60% dispersion in mineral oil; 47 mg,1.96 mmol; Aldrich) in one portion. After stirring for 30 minutes,6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (166 mg, 0.819 mmol,Maybridge) was added, and the solution was heated to 60° C. overnight.After the solvent was removed, the residue was treated with HCl inacetone/water (3 N, acetone:water=3:1, 20 mL), and the mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated in vacuo, and the residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.84-2.12(m, 4H) 2.95-3.16 (m, 2H) 3.16-3.38 (m, 3H) 4.32 (s, 2H) 5.47 (s, 2H)7.03 (d, J=9.49 Hz, 1H) 7.06-7.20 (m, 2H) 7.28-7.34 (m, 1H) 7.36 (s, 1H)7.42 (d, J=7.80 Hz, 1H) 7.82 (d, J=10.17 Hz, 1H); MS (ESI)⁺ m/z 378(M+H)⁺.

Example 2586′-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,2′-bipyridin-2-one

A 10 mL microwave reaction tube was charged with9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (231 mg,1.0 mmol; Example 161), 1-(6-bromopyridin-2-yl)pyridin-2(1H)-one (252mg, 1.0 mmol; Combi-phos), bis(tri-t-butylphosphine)palladium(0) (25.6mg, 0.05 mmol; Aldrich) and anhydrous dioxane (4 mL). The vessel wasflushed with nitrogen and sodium tert-butoxide (240 mg, 2.5 mmol;Aldrich) was added. After purging the reaction mixture with nitrogenagain, it was sealed and heated to 180° C. in a microwave reactor(Biotage Personal Chemistry™, Maximum 300 Watts) with stirring for 30minutes. The mixture was cooled and quenched with water, and thenextracted with ethyl acetate. The organic phase was concentrated andpurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer(0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammoniumhydroxide)] to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.97-2.24 (m, 4H) 3.05-3.28 (m, 5H) 4.26 (s, 2H) 6.46-6.53 (m, 1H)6.66 (d, J=9.16 Hz, 1H) 6.90 (td, J=9.16, 2.37 Hz, 1H) 7.09 (dd, J=9.32,2.20 Hz, 1H) 7.44 (dd, J=9.16, 4.07 Hz, 1H) 7.57 (d, J=7.12 Hz, 1H)7.59-7.66 (m, 1H) 7.80 (d, J=7.12 Hz, 1H) 7.89 (dd, J=7.46, 1.70 Hz, 1H)8.17-8.27 (m, 1H); MS (DCI/NH₃) m/z 401 (M+H)⁺.

Example 2596-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (231 mg,1.0 mmol; Example 161) and 6-bromoquinazolin-4-ol (225 mg, 1.0 mmol; ArkPharm) was performed as described in Example 258. The reaction waspurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer(0.1% trifluoroacetic acid)] to afford the title compound as thetrifluoroacetic acid salt: ¹H NMR (300 MHz, methanol-d₄) δ ppm 2.28-2.38(m, 4H) 3.13-3.19 (m, 1H) 3.55-3.76 (m, 4H) 6.97 (td, J=9.16, 2.37 Hz,1H) 7.13 (dd, J=9.16, 4.41 Hz, 1H) 7.24 (dd, J=9.16, 2.03 Hz, 1H)7.83-7.89 (m, 1H) 7.94-7.98 (m, 1H) 8.19 (d, J=2.03 Hz, 1H) 8.23 (s,1H); MS (DCI/NH₃) m/z 375 (M+H)⁺.

Example 2607-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinoxalin-2(1H)-one

The reaction of9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (231 mg,1.0 mmol; Example 161) and 7-bromoquinoxalin-2(1H)-one (225 mg, 1.0mmol; Ark Pharm) was performed as described in Example 259 to afford thetitle compound as the trifluoroacetic acid salt: ¹H NMR (300 MHz,methanol-d₄) δ ppm 2.29-2.39 (m, 4H) 3.21-3.28 (m, 1H) 3.54-3.76 (m, 4H)6.98 (td, J=9.16, 2.37 Hz, 1H) 7.18-7.26 (m, 2H) 7.32-7.41 (m, 2H) 8.06(d, J=8.48 Hz, 1H) 8.28 (s, 1H); MS (DCI/NH₃) m/z 375 (M+H)⁺.

Example 2617-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-oneExample 261A5-((5-bromopyridin-2-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

To a suspension of 5-bromopyridin-2-amine (4.97 g, 28.7 mmol; Aldrich)and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.55 g, 31.6 mmol; Aldrich) inethanol (100 mL) was added trimethoxymethane (3.35 g, 31.6 mmol;Aldrich) and mixture was heated to 100° C. with stirring for 30 minutes.Then the ethanol was blown off with a stream of nitrogen, and theresidual solid was permitted to cool to ambient temperature. The solidwas recrystallized from acetonitrile to afford the title compound: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.76 (s, 6H) 6.94 (d, J=8.73 Hz, 1H) 7.86(dd, J=8.72, 2.38 Hz, 1H) 8.47 (d, J=2.38 Hz, 1H) 9.33 (d, J=13.09 Hz,1H) 11.30 (d, J=13.09 Hz, 1H); MS (DCI/NH₃) m/z 344, 346 (M+NH₄)⁺.

Example 261B 7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one

5-((5-Bromopyridin-2-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(7.4 g, 22.62 mmol; Example 261A) in diphenyl ether (150 mL; Alfa Aesar)was heated to 200° C. with stirring for 3 hours. The mixture waspurified on a 340 gram silica gel column and washed with hexane firstand then eluted with hexane/ethyl acetate (2:3) to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 6.49 (d, J=6.44 Hz, 1H)7.62 (d, J=9.49 Hz, 1H) 8.03 (dd, J=9.49, 2.37 Hz, 1H) 8.32 (d, J=6.44Hz, 1H) 9.18 (d, J=1.70 Hz, 1H); MS (DCI/NH₃) m/z 225, 227 (M+H)⁺.

Example 261C7-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

A 10 mL microwave reaction tube was charged with9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (231 mg,1.0 mmol; Example 161), 7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one (338 mg,1.5 mmol; Example 261B), copper(I) iodide (19 mg, 0.1 mmol; Aldrich),trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexane-diamine (57 mg, 0.4 mmol,Acros) and dry toluene (3 mL). The vessel was flushed with nitrogen andpotassium phosphate tribasic (446 mg, 2.1 mmol; Aldrich) was added.After purging the reaction mixture with nitrogen again, it was sealedand heated to 110° C. with stirring for 20 hours. The mixture was cooledand quenched with water, and then extracted with ethyl acetate. Theorganic phase was concentrated and purified by reverse-phase HPLC[Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute,20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.96-2.21 (m, 4H)2.91-3.00 (m, 1H) 3.07-3.28 (m, 4H) 4.29 (s, 2H) 6.54 (d, J=6.44 Hz, 1H)6.90 (td, J=9.16, 2.71 Hz, 1H) 7.11-7.21 (m, 2H) 7.83-7.89 (m, 1H)7.92-7.99 (m, 1H) 8.39 (d, J=6.44 Hz, 1H) 9.07 (d, J=1.70 Hz, 1H); MS(DCI/NH₃) m/z 375 (M+H)⁺.

Example 2622-[6-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)pyridin-3-yl]pyridazin-3(2H)-oneExample 262A6-(5-bromopyridin-2-yl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

9-Fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (1.4 g,6.08 mmol, Example 161), 5-bromo-2-iodopyridine (2.59 g, 9.12 mmol),copper(I) iodide (0.116 g, 0.608 mmol), and cesium acetate (2.334 g,12.16 mmol) were dissolved in dry dimethyl sulfoxide (30 mL). Thereaction vial was evacuated then back-filled with dry N₂. The sealedvial was heated at 90° C. overnight. The reaction mixture was cooled toroom temperature, and then ethyl acetate (25 mL) and brine/14.8 Maqueous NH₄OH (8:2, 20 mL) were added. The solution was stirred for 15minutes and then filter through a bed of diatomaceous earth. The ethylacetate was removed, and then the aqueous layer was extracted with moreethyl acetate (2×25 mL). The combined organic extracts were dried overMgSO₄, and then the solid was removed by filtration. Volatiles wereremoved in vacuo. The crude residue was purified by flash chromatography[100% CH₂Cl₂ for 5 minutes followed by a gradient from 0 to 100%CH₂Cl₂/methanol/14.8 M aqueous NH₄OH (78:20:2) in CH₂Cl₂ for 15 minutesand then held at 100% CH₂Cl₂/methanol/14.8 M aqueous NH₄OH (78:20:2) for5 minutes] to give the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm1.89-2.08 (m, 2H) 2.07-2.26 (m, 2H) 3.18 (s, 3H) 3.25-3.46 (m, 2H) 4.34(s, 2H) 6.84-6.97 (m, 1H) 7.00-7.10 (m, 1H) 7.22 (s, 1H) 7.29-7.38 (m,1H) 8.00 (d, J=10.85 Hz, 1H) 8.70 (s, 1H); MS (ESI) m/z 287 (M+H)⁺.

Example 262B2-[6-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)pyridin-3-yl]pyridazin-3(2H)-one

A sealed tube was charged with the product from Example 262A (390 mg,1.01 mmol), pyridazin-3(2H)-one (97 mg, 1.01 mmol; Fluka), copper (64mg, 1.01 mmol; Aldrich), copper (I) iodide (288 mg, 1.32 mmol; Aldrich),K₂CO₃ (419 mg, 3.03 mmol; Aldrich) and pyridine (5.0 mL). The tube wasflushed with N₂ (2×). N,N′-Dimethyl-ethylenediamine (0.033 mL, 0.303mmol) was added to the tube and it was heated to 117° C. for 72 hours.Volatiles were removed under reduced pressure. The residue waspartitioned between CHCl₃ and 14.8 M aqueous NH₄OH_(aq). The organiclayer was dried over MgSO₄, and the solid was removed by filtration. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby reverse-phase HPLC [Waters XBridge™ C 18 5 μm OBD column, 30×100 mm,flow rate 40 mL/minute, 20-95% gradient of methanol in buffer (0.1 Maqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)over 20 minutes] to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δppm 1.87-2.10 (m, 2H) 2.08-2.31 (m, 2H) 3.07-3.48 (m, 5H) 4.26-4.47 (m,2H) 6.78-7.02 (m, 1H) 7.02-7.17 (m, 2H) 7.32 (dd, J=9.49, 4.07 Hz, 1H)7.38-7.49 (m, 2H) 7.99 (d, J=3.73 Hz, 1H) 8.28 (dd, J=8.48, 2.71 Hz, 1H)8.98 (d, J=2.71 Hz, 1H); MS (ESI) m/z 402 (M+H)⁺.

Example 2639-fluoro-6-(2-methylpyrimidin-5-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A sealed tube was charged9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (130 mg,0.565 mmol, Example 161), 5-bromo-2-methylpyrimidine (98 mg, 0.565 mmol;Anichem), copper (36 mg, 0.565 mmol; Aldrich), copper (I) iodide (161mg, 0.847 mmol; Aldrich), K₂CO₃ (234 mg, 1.69 mmol; Aldrich), andpyridine (5.0 mL). The tube was flushed with N₂ (2×).N,N′-Dimethyl-ethylenediamine (0.033 mL, 0.303 mmol) was added to thetube, and the mixture was heated to 117° C. for 72 hours. Volatiles wereremoved under reduced pressure. The residue was partitioned betweenCHCl₃ and 14.8 M aqueous NH₄OH. The organic layer was dried over MgSO₄and then the solid was removed by filtration. The reaction mixture wasconcentrated in vacuo, and the residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes]to afford the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.83-2.16(m, 4H) 2.71-2.80 (m, 1H) 2.86 (s, 3H) 3.03-3.24 (m, 2H) 3.22-3.41 (m,2H) 4.29 (s, 2H) 6.83-6.94 (m, 1H) 6.94-7.03 (m, 1H) 7.05-7.15 (m, 1H)8.63 (s, 2H); MS (ESI) m/z 323 (M+H)⁺.

Example 2649-fluoro-6-(pyridin-3-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

A sealed tube was charged with9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (130 mg,0.565 mmol, Example 161), 3-bromopyridine (98 mg, 0.565 mmol; Aldrich),copper (36 mg, 0.565 mmol; Aldrich), copper (I) iodide (161 mg, 0.847mmol; Aldrich), K₂CO₃ (234 mg, 1.69 mmol; Aldrich) and pyridine (5.0mL). The tube was flushed with N₂ (2×). N,N′-Dimethyl-ethylenediamine(0.018 mL, 0.169 mmol) was added to the tube and the reaction mixturewas heated to 117° C. for 72 hours. Volatiles were removed under reducedpressure. The residue was partitioned between CHCl₃ and 14.8 M aqueousNH₄OH. The organic layer was dried over MgSO₄, and then the solid wasremoved by filtration. The reaction mixture was concentrated in vacuo,and the residue was purified by reverse-phase HPLC [Waters XBridge™ C185 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide) over 20 minutes] to afford the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.80-2.17 (m, 4H) 2.74-2.93 (m,1H) 3.03-3.24 (m, 2H) 3.25-3.46 (m, 2H) 4.32 (s, 2H) 6.80-6.93 (m, 1H)7.00 (dd, J=8.92, 4.16 Hz, 1H) 7.09 (d, J=9.52 Hz, 1H) 7.51 (dd, J=7.93,4.76 Hz, 1H) 7.63-7.72 (m, 1H) 8.60 (s, 1H) 8.71 (d, J=1.19 Hz, 1H); MS(ESI) m/z 308 (M+H)⁺.

Example 2656-[6-(morpholin-4-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 4-(6-bromopyrid-2-yl)morpholine(243 mg, 1.0 mmol; Combi-Blocks) was performed using the methodologydescribed in Example 258 to afford the title compound: ¹H NMR (300 MHz,methanol-d₄) δ ppm 1.94-2.23 (m, 4H) 3.05-3.29 (m, 5H) 3.50-3.56 (m, 4H)3.73-3.83 (m, 4H) 4.30 (s, 2H) 6.72 (d, J=7.12 Hz, 1H) 6.80 (d, J=8.48Hz, 1H) 7.03-7.13 (m, 2H) 7.33-7.42 (m, 2H) 7.72-7.80 (m, 1H); MS(DCI/NH₃) m/z 375 (M+H)⁺.

Example 2666-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)nicotinamide

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and 6-bromonicotinonitrile (183 mg, 1.0mmol; Aldrich) was performed using the methodology described in Example258 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.97-2.25 (m, 4H) 3.04-3.29 (m, 5H) 4.32 (s, 2H) 7.10-7.19 (m, 2H)7.38-7.47 (m, 2H) 7.55 (d, J=9.16 Hz, 1H) 8.45 (dd, J=8.31, 2.54 Hz, 1H)9.08 (d, J=1.70 Hz, 1H); MS (DCI/NH₃) m/z 333 (M+H)⁺.

Example 2676-(1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(162 mg, 0.76 mmol; Example 187A) and tert-butyl6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (238 mg, 0.76 mmol;Anthem Biosciences) was performed using the methodology described inExample 258 to afford tert-butyl6-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.This compound was treated with trifluoroacetic acid (1 mL) in CH₂Cl₂ (4mL) at room temperature with stirring for 16 hours. After concentration,the mixture was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μmOBD column, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide)] to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.92-2.13 (m, 4H) 2.91 (t, J=5.16 Hz, 3H)3.06-3.29 (m, 6H) 4.06 (s, 2H) 4.32 (s, 2H) 6.98-7.11 (m, 5H) 7.23-7.28(m, 1H) 7.34-7.40 (m, 1H); MS (DCI/NH₃) m/z 344 (M+H)⁺.

Example 2686-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

6-(1,2,3,4-Tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(70 mg, 0.20 mmol; Example 267), 37% formaldehyde (50 mg, 0.62 mmol; J.T. Baker) and sodium triacetoxyborohydride (130 mg, 0.61 mmol; Aldrich)were mixed in acetonitrile (4 mL) at room temperature with stirring for4 hours. The mixture was purified by reverse-phase HPLC [Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-99% gradientof methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted topH 10 with ammonium hydroxide)] to afford the title compound: ¹H NMR(300 MHz, methanol-d₄) δ ppm 1.92-2.13 (m, 4H) 2.51 (s, 3H) 2.80 (t,J=5.95 Hz, 2H) 2.86-2.93 (m, 1H) 2.99-3.28 (m, 6H) 3.71 (s, 2H) 4.31 (s,2H) 6.97-7.13 (m, 5H) 7.27 (d, J=7.54 Hz, 1H) 7.34-7.40 (m, 1H); MS(DCI/NH₃) m/z 358 (M+H)⁺.

Example 2696-(quinazolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(110 mg, 0.52 mmol; Example 187A) and 6-bromoquinazoline (162 mg, 0.78mmol; Parkway) was performed using the methodology described in Example258 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.95-2.24 (m, 4H) 2.93-3.02 (m, 1H) 3.08-3.29 (m, 4H) 4.36 (s, 2H)7.07-7.21 (m, 3H) 7.38-7.49 (m, 1H) 8.00 (dd, J=8.73, 2.38 Hz, 1H) 8.15(d, J=2.38 Hz, 1H) 8.24 (d, J=8.73 Hz, 1H) 9.34 (s, 1H) 9.64 (s, 1H); MS(DCI/NH₃) m/z 341 (M+H)⁺.

Example 2706-(isoquinolin-7-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(112 mg, 0.53 mmol; Example 187A) and 7-bromoisoquinoline (165 mg, 0.79mmol; Frontier) was performed using the methodology described in Example258 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm1.94-2.22 (m, 4H) 2.91-3.00 (m, 1H) 3.09-3.29 (m, 4H) 4.36 (s, 2H)7.06-7.15 (m, 3H) 7.40-7.46 (m, 1H) 7.75 (dd, J=8.48, 2.03 Hz, 1H) 7.95(d, J=5.76 Hz, 1H) 8.11 (d, J=2.03 Hz, 1H) 8.16 (d, J=8.82 Hz, 1H) 8.54(d, J=5.76 Hz, 1H) 9.34 (s, 1H); MS (DCI/NH₃) m/z 340 (M+H)⁺.

Example 2716-(isoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(112 mg, 0.53 mmol; Example 187A) and 6-bromoisoquinoline (165 mg, 0.79mmol; Accela ChemBio) was performed using the methodology described inExample 258 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.96-2.22 (m, 4H) 2.99 (ddd, J=7.38, 5.00, 2.20 Hz, 1H) 3.09-3.29(m, 4H) 4.35 (s, 2H) 7.06-7.20 (m, 3H) 7.39-7.47 (m, 1H) 7.65 (dd,J=8.48, 2.03 Hz, 1H) 7.89-7.97 (m, 2H) 8.32 (d, J=8.48 Hz, 1H) 8.52 (d,J=5.76 Hz, 1H) 9.35 (s, 1H); MS (DCI/NH₃) m/z 340 (M+H)⁺.

Example 2726-[4-(1H-imidazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(112 mg, 0.53 mmol; Example 187A) and2-bromo-4-(1H-imidazol-1-yl)pyridine (118 mg, 0.53 mmol; Combi-Phos) wasperformed using the procedure described in Example 258 to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.97-2.10 (m, 2H)2.14-2.31 (m, 2H) 3.07-3.29 (m, 5H) 4.32 (s, 2H) 7.09-7.19 (m, 2H) 7.23(s, 1H) 7.36-7.45 (m, 2H) 7.72-7.77 (m, 1H) 7.77-7.80 (m, 1H) 7.85 (t,J=1.53 Hz, 1H) 8.50 (s, 1H) 8.71 (d, J=5.09 Hz, 1H); MS (DCI/NH₃) m/z356 (M+H)⁺.

Example 2736′-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,2′-bipyridin-2-one

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(112 mg, 0.53 mmol; Example 187A) and1-(6-bromopyridin-2-yl)pyridin-2(1H)-one (132 mg, 0.53 mmol; Combi-Phos)was performed using the procedure described in Example 258 to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 2.02-2.29 (m, 4H)3.15-3.40 (m, 5H) 4.41 (s, 2H) 6.50 (t, J=6.74 Hz, 1H) 6.66 (d, J=9.12Hz, 1H) 7.11-7.21 (m, 2H) 7.39-7.52 (m, 2H) 7.59-7.67 (m, 2H) 7.80 (d,J=7.93 Hz, 1H) 7.90 (dd, J=6.74, 1.98 Hz, 1H) 8.23 (t, J=7.93 Hz, 1H);MS (DCI/NH₃) m/z 383 (M+H)⁺.

Example 2747-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinoxalin-2(1H)-one

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(127 mg, 0.60 mmol; Example 187A) and 7-bromoquinoxalin-2(1H)-one (203mg, 0.90 mmol; Ark Pharm) was performed using the procedure described inExample 258 to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.98-2.20 (m, 4H) 3.03 (ddd, J=7.29, 4.92, 2.37 Hz, 1H) 3.10-3.30(m, 4H) 4.35 (s, 2H) 7.07-7.14 (m, 2H) 7.15-7.21 (m, 1H) 7.27-7.34 (m,2H) 7.38-7.45 (m, 1H) 8.00 (d, J=8.48 Hz, 1H) 8.23 (s, 1H); MS (DCI/NH₃)m/z 357 (M+H)⁺.

Example 2757-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,4-benzoxazin-3(4H)-one

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (228 mg, 1.0 mmol; Biogene) wasperformed using the procedure described in Example 258 to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.95-2.12 (m, 4H)2.92 (ddd, J=7.29, 4.75, 2.54 Hz, 1H) 3.05-3.28 (m, 4H) 4.31 (s, 2H)4.66 (s, 2H) 6.90-6.95 (m, 2H) 7.02-7.09 (m, 4H) 7.35-7.40 (m, 1H); MS(DCI/NH₃) m/z 360 (M+H)⁺.

Example 2762-amino-5-(3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-6(1H)-yl)benzamideExample 276A6-(3-cyano-4-nitrophenyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

3,4,5,6-Tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (425 mg, 2.0 mmol;Example 187A) in N,N-dimethylformamide (10 mL) was treated with 60%dispersion in oil of NaH (101 mg, 4.2 mmol; Aldrich) at roomtemperature. The mixture was stirred for 30 minutes, and then5-fluoro-2-nitrobenzonitrile (415 mg, 2.5 mmol; Oakwood) was added. Themixture was stirred for 3 more hours before being quenched withmethanol. The mixture was purified by flash chromatography (200 silicagel, CH₂Cl₂/methanol 10:1) to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 2.08-2.29 (m, 4H) 3.02-3.10 (m, 1H) 3.21-3.49(m, 4H) 4.50 (s, 2H) 7.17-7.29 (m, 3H) 7.44-7.49 (m, 1H) 7.91 (dd,J=8.82, 2.37 Hz, 1H) 8.08 (d, J=2.37 Hz, 1H) 8.59 (d, J=8.82 Hz, 1H); MS(DCI/NH₃) m/z 359 (M+H)⁺.

Example 276B2-amino-5-(3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indol-6(1H)-yl)benzamide

6-(3-Cyano-4-nitrophenyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(500 mg, 1.395 mmol; Example 276A) and 10% Pd/C (100 mg; Aldrich) weremixed in methanol (15 mL). The mixture was subjected to hydrogenationunder a balloon of hydrogen at room temperature with stirring for 1.5hours. After the catalyst was removed by filtration, the filtrate wasconcentrated, and the residue was purified by reverse-phase HPLC [WatersXBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-99%gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate,adjusted to pH 10 with ammonium hydroxide)] to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.96-2.15 (m, 4H)2.87-2.93 (m, 1H) 3.06-3.29 (m, 4H) 4.33 (s, 2H) 6.90 (d, J=8.48 Hz, 1H)6.98-7.07 (m, 3H) 7.11 (dd, J=8.48, 2.37 Hz, 1H) 7.34-7.39 (m, 1H) 7.51(d, J=2.37 Hz, 1H); MS (DCI/NH₃) m/z 347 (M+H)⁺.

Example 2777-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(212 mg, 1.0 mmol; Example 187A) and7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one (341 mg, 1.5 mmol; Example 261B)was performed using the procedure described in Example 261C to affordthe title compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.98-2.22 (m,4H) 2.95-3.02 (m, 1H) 3.08-3.29 (m, 4H) 4.34 (s, 2H) 6.54 (d, J=6.44 Hz,1H) 7.11-7.26 (m, 3H) 7.41-7.49 (m, 1H) 7.82-7.92 (m, 1H) 7.93-8.01 (m,1H) 8.37-8.41 (m, 1H) 9.07 (d, J=1.70 Hz, 1H); MS (DCI/NH₃) m/z 357(M+H)⁺.

Example 278(7S,10R)-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indoleExample 278A 5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

In a 30 mL round-bottomed microwave reaction tube were combinedphenylhydrazine hydrochloride (3.51 g, 24.4 mmol; Aldrich), tert-butyl3-oxo-6-azabicyclo[3.1.1]heptane-6-carboxylate (5.5 g, 24.4 mmol;Chireach) and 1 N HCl in acetic acid (15 mL; Aldrich). The reactionmixture was heated to 150° C. with stirring for 15 minutes in amicrowave reactor (Biotage Personal Chemistry™, maximum 300 Watts), andthen cooled to room temperature. The reaction mixture was concentrated,and the residue was purified by flash chromatography (silica gel, elutedwith CH₂Cl₂/methanol 10:1) to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.59-1.70 (m, 1H) 1.94-2.22 (m, 3H) 2.54 (dd,J=16.28, 1.36 Hz, 1H) 3.25 (dd, J=16.28, 4.41 Hz, 1H) 3.90-3.98 (m, 1H)4.50 (d, J=4.75 Hz, 1H) 6.91-7.02 (m, 2H) 7.21-7.25 (m, 1H) 7.36-7.42(m, 1H); MS (DCI/NH₃) m/z 199 (M+H)⁺.

Example 278B tert-butyl5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate

5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (4.8 g, 24.21mmol; Example 276A), di-tert-butyl dicarbonate (5.81 g, 26.6 mmol;Fluka) and triethylamine (10.12 mL, 72.6 mmol; Aldrich) were mixed indichloromethane (60 mL; Aldrich), and the mixture was stirred at roomtemperature for 16 hours. After being concentrated, the residue waspurified on a flash chromatography (silica gel, eluted with hexane/ethylacetate 3:2) to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.28-1.49 (m, 9H) 1.64-1.77 (m, 1H) 1.86-1.97 (m, 1H) 2.10-2.40(m, 2H) 2.54 (d, J=16.26 Hz, 1H) 3.34-3.50 (m, 1H) 4.56 (dd, J=7.93,4.36 Hz, 1H) 5.19 (d, J=5.16 Hz, 1H) 6.92-7.08 (m, 2H) 7.25 (d, J=6.74Hz, 1H) 7.41 (d, J=7.54 Hz, 1H); MS (DCI/NH₃) m/z 299 (M+H)⁺.

Example 278C tert-butyl5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate

The reaction of tert-butyl5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate(597 mg, 2.0 mmol; Example 278B) and 6-bromoquinoline (624 mg, 3.0 mmol;Aldrich) was performed as described in Example 261C to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.35-1.50 (m, 9H)1.67-1.82 (m, 1H) 2.01-2.09 (m, 1H) 2.15-2.54 (m, 3H) 3.34-3.49 (m, 1H)4.61 (dd, J=7.46, 4.41 Hz, 1H) 5.33 (d, J=4.75 Hz, 1H) 7.08-7.18 (m, 2H)7.22-7.30 (m, 1H) 7.55-7.66 (m, 2H) 7.79 (dd, J=8.82, 2.37 Hz, 1H) 7.97(d, J=2.37 Hz, 1H) 8.22 (d, J=8.82 Hz, 1H) 8.46 (d, J=8.48 Hz, 1H) 8.93(dd, J=4.07, 1.70 Hz, 1H); MS (DCI/NH₃) m/z 426 (M+H)⁺.

Example 278D5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

tert-Butyl5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate(440 mg, 1.03 mmol; Example 278C) was dissolved in dichloromethane (8mL; Aldrich) and treated with trifluoroacetic acid (1.5 mL; Aldrich) atroom temperature with stirring for 16 hours. The mixture wasconcentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient ofmethanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH10 with ammonium hydroxide)] to afford the title compound: ¹H NMR (300MHz, methanol-d₄) δ ppm 1.64-1.80 (m, 1H) 2.09-2.28 (m, 3H) 2.50 (d,J=16.66 Hz, 1H) 3.31-3.38 (m, 1H) 4.05 (t, J=4.96 Hz, 1H) 4.72 (t,J=4.36 Hz, 1H) 7.07-7.17 (m, 2H) 7.23-7.31 (m, 1H) 7.53-7.59 (m, 1H)7.62 (dd, J=8.33, 4.36 Hz, 1H) 7.83 (dd, J=8.72, 2.38 Hz, 1H) 7.99 (d,J=1.98 Hz, 1H) 8.21 (d, J=8.72 Hz, 1H) 8.45 (d, J=8.33 Hz, 1H) 8.92 (dd,J=4.36, 1.98 Hz, 1H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 278E(7S,10R)-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the mixture of5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(240 mg, 0.74 mmol; Example 278D) were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-30% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to obtain the title compound as the second eluting peak (retentiontime=14.7 minutes): ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.60-1.77 (m,1H) 2.06-2.25 (m, 3H) 2.41-2.52 (m, 1H) 3.26-3.36 (m, 1H) 4.00 (t,J=4.92 Hz, 1H) 4.66 (d, J=3.39 Hz, 1H) 7.05-7.16 (m, 2H) 7.22-7.30 (m,1H) 7.51-7.59 (m, 1H) 7.59-7.66 (m, 1H) 7.83 (dd, J=8.82, 2.37 Hz, 1H)7.98 (d, J=2.37 Hz, 1H) 8.21 (d, J=8.82 Hz, 1H) 8.42-8.48 (m, 1H) 8.92(dd, J=4.41, 1.70 Hz, 1H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 279(7R,10S)-5-(isoquinolin-7-yl)-6,7,8,9,10-pentahydro-7,10-epiminocyclohepta[b]indoleExample 279A tert-butyl5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate

The reaction of tert-butyl5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate(597 mg, 2.0 mmol; Example 278B) and 7-bromoisoquinoline (624 mg, 3.0mmol; Aldrich) was performed as described in Example 261C to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.35-1.50 (m, 9H)1.69-1.82 (m, 1H) 2.00-2.08 (m, 1H) 2.17-2.40 (m, 2H) 2.46 (d, J=16.28Hz, 1H) 3.36-3.49 (m, 1H) 4.61 (dd, J=7.12, 4.41 Hz, 1H) 5.33 (d, J=5.09Hz, 1H) 7.09-7.19 (m, 2H) 7.22-7.31 (m, 1H) 7.54-7.63 (m, 1H) 7.78-7.83(m, 1H) 7.93 (d, J=5.76 Hz, 1H) 8.11-8.18 (m, 2H) 8.52 (d, J=6.10 Hz,1H) 9.33 (s, 1H); MS (DCI/NH₃) m/z 426 (M+H)⁺.

Example 279B5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

tert-Butyl5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate(624 mg, 1.47 mmol; Example 279A) was dissolved in dichloromethane (10mL) and treated with trifluoroacetic acid (2.0 mL; Aldrich) at roomtemperature with stirring for 16 hours. The mixture was concentrated andpurified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer(0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammoniumhydroxide)] to afford the title compound: ¹H NMR (300 MHz, methanol-d₄)δ ppm 1.63-1.78 (m, 1H) 2.07-2.27 (m, 3H) 2.48 (d, J=16.66 Hz, 1H)3.27-3.36 (m, 1H) 4.03 (t, J=5.16 Hz, 1H) 4.69 (d, J=3.57 Hz, 1H)7.07-7.17 (m, 2H) 7.23-7.31 (m, 1H) 7.52-7.62 (m, 1H) 7.84 (dd, J=8.73,1.98 Hz, 1H) 7.93 (d, J=5.95 Hz, 1H) 8.11-8.19 (m, 2H) 8.52 (d, J=5.55Hz, 1H) 9.33 (s, 1H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 279C(7R,10S)-5-(isoquinolin-7-yl)-6,7,8,9,10-pentahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the mixture of5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(350 mg, 1.07 mmol; Example 279B) were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-30% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to obtain the title compound as the first eluting peak (retentiontime=12.2 minutes): ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.64-1.76 (m,1H) 2.06-2.28 (m, 3H) 2.47 (dd, J=16.62, 1.36 Hz, 1H) 3.25-3.34 (m, 1H)4.02 (t, J=5.09 Hz, 1H) 4.68 (d, J=3.39 Hz, 1H) 7.06-7.16 (m, 2H)7.22-7.30 (m, 1H) 7.53-7.62 (m, 1H) 7.84 (dd, J=8.82, 2.03 Hz, 1H) 7.93(d, J=5.76 Hz, 1H) 8.12-8.18 (m, 2H) 8.51 (d, J=6.10 Hz, 1H) 9.33 (s,1H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 280(7S,10R)-5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the mixture of5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(350 mg, 1.07 mmol; Example 279B) were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-30% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to obtain the title compound as the second eluting peak (retentiontime=14.3 minutes): ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.60-1.76 (m,1H) 2.04-2.25 (m, 3H) 2.45 (d, J=16.66 Hz, 1H) 3.25-3.34 (m, 1H) 3.99(t, J=4.96 Hz, 1H) 4.65 (d, J=3.57 Hz, 1H) 7.06-7.17 (m, 2H) 7.22-7.30(m, 1H) 7.52-7.60 (m, 1H) 7.84 (dd, J=8.72, 1.98 Hz, 1H) 7.93 (d, J=5.55Hz, 1H) 8.11-8.17 (m, 2H) 8.51 (d, J=5.95 Hz, 1H) 9.32 (s, 1H); MS(DCI/NH₃) m/z 326 (M+H)⁺.

Example 281(7S,10R)-11-methyl-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

(7S,10R)-5-(Quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(110 mg, 0.338 mmol; Example 278E) in acetonitrile (2 mL) and water (2mL) was treated with a 37% aqueous solution of formaldehyde (0.4 mL; J.T. Baker) and then sodium triacetoxyborohydride (179 mg, 0.845 mmol;Aldrich). The mixture was stirred at room temperature for 2 hours. Afterbeing concentrated, the residue was purified by reverse-phase HPLC[Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute,20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.62-1.78 (m, 1H)1.96-2.06 (m, 1H) 2.22-2.52 (m, 6H) 3.22-3.29 (m, 1H) 3.56-3.63 (m, 1H)4.33 (d, J=5.16 Hz, 1H) 7.06-7.16 (m, 2H) 7.22-7.35 (m, 1H) 7.50-7.59(m, 1H) 7.62 (dd, J=8.72, 4.36 Hz, 1H) 7.84 (dd, J=9.12, 2.38 Hz, 1H)8.00 (d, J=2.38 Hz, 1H) 8.21 (d, J=8.73 Hz, 1H) 8.46 (d, J=8.33 Hz, 1H)8.92 (dd, J=4.36, 1.59 Hz, 1H); MS (DCI/NH₃) m/z 340 (M+H)⁺.

Example 282(7R,10S)-5-(quinolin-6-yl)-5,6,7,8,9,1-hexahydro-7,10-epiminocyclohepta[b]indole

The individual enantiomers from the mixture of5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(240 mg, 0.74 mmol; Example 278D) were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-30% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to obtain the title compound as the first eluting peak (retentiontime=11.7 minutes): ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.59-1.77 (m,1H) 2.05-2.25 (m, 3H) 2.40-2.50 (m, 1H) 3.25-3.31 (m, 1H) 3.99 (t,J=5.09 Hz, 1H) 4.64 (d, J=3.39 Hz, 1H) 7.06-7.15 (m, 2H) 7.21-7.30 (m,1H) 7.51-7.59 (m, 1H) 7.62 (dd, J=8.31, 4.24 Hz, 1H) 7.78-7.88 (m, 1H)7.98 (d, J=2.37 Hz, 1H) 8.20 (d, J=9.16 Hz, 1H) 8.45 (d, J=7.46 Hz, 1H)8.92 (dd, J=4.07, 1.70 Hz, 1H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 2837-[(7S,10R)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-oneExample 283At-butyl-5-(4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate

The reaction of tert-butyl5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate(448 mg, 1.5 mmol; Example 278B) and7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one (506 mg, 2.25 mmol; Example261B) was performed as described in Example 261C to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.40 (s, 9H) 1.69-1.82 (m,1H) 2.04 (t, J=9.16 Hz, 1H) 2.16-2.41 (m, 2H) 2.50 (d, J=16.28 Hz, 1H)3.42 (d, J=13.90 Hz, 1H) 4.63 (dd, J=7.63, 4.58 Hz, 1H) 5.31 (d, J=5.09Hz, 1H) 6.53 (d, J=6.44 Hz, 1H) 7.14-7.23 (m, 2H) 7.29-7.37 (m, 1H) 7.60(dd, J=5.59, 3.22 Hz, 1H) 7.87 (d, J=9.49 Hz, 1H) 8.05 (d, J=9.16 Hz,1H) 8.38 (d, J=6.44 Hz, 1H) 9.09 (d, J=2.37 Hz, 1H); MS (DCI/NH₃) m/z443 (M+H)⁺.

Example 283B7-(7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

The reaction oft-butyl-5-(4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate(350 mg, 0.79 mmol; Example 283A) and trifluoroacetic acid (2 mL;Aldrich) was performed as described in Example 278D to afford the titlecompound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.65-1.81 (m, 1H)2.05-2.28 (m, 3H) 2.53 (d, J=16.62 Hz, 1H) 3.23-3.36 (m, 1H) 4.04-4.13(m, 1H) 4.70 (s, 1H) 6.53 (d, J=6.44 Hz, 1H) 7.13-7.20 (m, 2H) 7.29-7.37(m, 1H) 7.54-7.62 (m, 1H) 7.86 (d, J=9.49 Hz, 1H) 8.07 (dd, J=9.16, 2.37Hz, 1H) 8.38 (d, J=6.44 Hz, 1H) 9.12 (d, J=1.70 Hz, 1H); MS (DCI/NH₃)m/z 343 (M+H)⁺.

Example 283C7-[(7S,10R)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one

The individual enantiomers from the mixture of7-(7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl)-4H-pyrido[1,2-a]pyrimidin-4-one(250 mg, 0.73 mmol; Example 283B) were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-30% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to obtain the title compound as the second eluting peak (retentiontime=15.2 minutes): ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.63-1.77 (m,1H) 2.03-2.26 (m, 3H) 2.45-2.56 (m, 1H) 3.24-3.33 (m, 1H) 3.95-4.09 (m,1H) 4.63 (d, J=3.73 Hz, 1H) 6.53 (d, J=6.10 Hz, 1H) 7.12-7.20 (m, 2H)7.28-7.38 (m, 1H) 7.52-7.62 (m, 1H) 7.86 (d, J=9.49 Hz, 1H) 8.08 (dd,J=9.49, 2.37 Hz, 1H) 8.38 (d, J=6.44 Hz, 1H) 9.12 (d, J=2.37 Hz, 1H); MS(DCI/NH₃) m/z 343 (M+H)⁺.

Example 2847-[(7R,10S)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one

The individual enantiomers from the mixture of5-(4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(250 mg, 0.73 mmol; Example 283B) were separated by preparative chiralsupercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250mm, 35° C., 10-30% gradient of CH₃OH—CO₂ containing 0.1% diethylamine)to obtain the title compound as the first eluting peak (retentiontime=12.7 minutes): ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.62-1.76 (m,1H) 2.02-2.28 (m, 3H) 2.48 (dd, J=16.28, 1.36 Hz, 1H) 3.23-3.32 (m, 1H)3.98-4.08 (m, 1H) 4.63 (d, J=4.07 Hz, 1H) 6.52 (d, J=6.44 Hz, 1H)7.10-7.21 (m, 2H) 7.28-7.38 (m, 1H) 7.53-7.61 (m, 1H) 7.86 (d, J=9.49Hz, 1H) 8.07 (dd, J=9.32, 2.54 Hz, 1H) 8.38 (d, J=6.10 Hz, 1H) 9.12 (d,J=2.03 Hz, 1H); MS (DCI/NH₃) m/z 343 (M+H)⁺.

Example 2856-[(6-chloropyridin-3-yl)methyl]-9-fluoro-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indoleExample 285A 2-chloro-5-((1-(4-fluorophenyl)hydrazinyl)methyl)pyridine

(4-Fluorophenyl)hydrazine hydrochloride (3.24 g, 20 mmol; Maybridge) and2-chloro-5-(chloromethyl)pyridine (3.24 g, 20.00 mmol; Aldrich) weremixed in ethanol (120 mL) and then treated with triethylamine (9.76 mL,70.0 mmol; Aldrich). The mixture was heated to 80° C. with stirring for16 hours. Then the solvent was removed and the residue was purified byflash chromatography (silica gel, CH₂Cl₂:methanol=10:1) to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 4.51-4.58 (m, 2H)6.82-7.10 (m, 4H) 7.40 (d, J=8.14 Hz, 1H) 7.77 (dd, J=8.31, 2.54 Hz, 1H)8.30 (d, J=2.71 Hz, 1H); MS (DCI/NH₃) m/z 237 (M+H)⁺.

Example 285B6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole

2-Chloro-5-((1-(4-fluorophenyl)hydrazinyl)methyl)pyridine (252 mg, 1.0mmol; Example 285A) and 6-azabicyclo[3.2.1]octan-3-one (125 mg, 1.0mmol; GLSyntech, LLC) were mixed in dioxane (8 mL) and then treated withsulfuric acid (0.107 mL, 2.000 mmol; J. T. Baker). The mixture washeated to 85° C. with stirring for 16 hours. The mixture was washed with1 N aqueous NaOH and extracted with methylene chloride, the organicphase was concentrated, and the residue was purified by reverse-phaseHPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40mL/minute, 20-99% gradient of methanol in buffer (0.1% trifluoroaceticacid)] to afford the title compound as the trifluoroacetic acid salt: ¹HNMR (300 MHz, methanol-d₄) δ ppm 2.18-2.37 (m, 2H) 3.07-3.17 (m, 1H)3.21-3.29 (m, 1H) 3.42-3.55 (m, 2H) 3.79 (s, 1H) 4.49-4.55 (m, 1H) 5.36(q, J=17.05 Hz, 2H) 6.91 (td, J=9.12, 2.78 Hz, 1H) 7.24-7.34 (m, 2H)7.36-7.41 (m, 1H) 7.44-7.52 (m, 1H) 8.13 (d, J=2.38 Hz, 1H); MS(DCI/NH₃) m/z 342 (M+H)⁺.

Example 286(7R,10S)-11-methyl-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole

(7R,10S)-5-(Quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole(90 mg, 0.277 mmol; Example 282) in acetonitrile (2 mL) and water (2 mL)was treated with a 37% aqueous solution of formaldehyde (0.4 mL; J. T.Baker) and then sodium triacetoxyborohydride (147 mg, 0.69 mmol;Aldrich). The mixture was stirred at room temperature for 2 hours. Afterbeing concentrated, the residue was purified by reverse-phase HPLC[Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute,20-99% gradient of methanol in buffer (0.1 M aqueous ammoniumbicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford thetitle compound: ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.62-1.78 (m, 1H)1.96-2.07 (m, 1H) 2.21-2.52 (m, 6H) 3.24 (m, 1H) 3.56-3.63 (m, 1H) 4.33(d, J=5.09 Hz, 1H) 7.06-7.16 (m, 2H) 7.24-7.33 (m, 1H) 7.50-7.57 (m, 1H)7.62 (dd, J=8.48, 4.41 Hz, 1H) 7.84 (dd, J=9.16, 2.37 Hz, 1H) 8.00 (d,J=2.37 Hz, 1H) 8.21 (d, J=8.82 Hz, 1H) 8.46 (d, J=7.80 Hz, 1H) 8.92 (dd,J=4.41, 1.70 Hz, 1H); MS (DCI/NH₃) m/z 340 (M+H)⁺.

Example 2872-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridazin-3(2H)-one

The reaction of6-(4-iodophenyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole(235 mg, 0.567 mmol; Example 239A) and pyridazin-3(2H)-one (82.0 mg,0.851 mmol; Fluka) was performed as described in Example 239B to affordthe title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.83-2.19 (m, 4H)2.96-3.10 (m, 1H) 3.11-3.28 (m, 2H) 3.27-3.52 (m, 2H) 4.42 (s, 2H)7.11-7.19 (m, 3H) 7.21 (t, J=3.73 Hz, 1H) 7.28-7.35 (m, 1H) 7.38-7.48(m, 3H) 7.83 (d, J=8.82 Hz, 2H) 7.95 (d, J=1.70 Hz, 1H); MS (DCI) m/z383 (M+H)⁺.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[6-(4-iodophenyl)pyridazin-3-yl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-methanoazepino[4,3-b]indole;2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-1,4-methanopyrido[4,3-b]indole;6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-4,1-(epiminomethano)carbazole;2,6-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-1,4-methano-β-carboline;6,11-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-1,4-(epiminomethano)carbazole;2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-6,9-epiminocyclohepta[b]indole;2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-6,10-epiminocycloocta[b]indole;6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-1,4-epiminocarbazole;2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,6-hexahydro-1,5-methanoazepino[4,3-b]indole;2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole;2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;(5aS*,7S*,10R*,10aR*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole;(5aR*,7S*,10R*,10aS*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole;(5aS*,7S*,11R*,11aR*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-7,11-epiminocycloocta[b]indole;(5aR*,7S*,11R*,11aS*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-7,11-epiminocycloocta[b]indole;(5R*,5aS*,10bR*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-methanoazepino[4,3-b]indole;(5R*,5aR*,10bS*)-9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-methanoazepino[4,3-b]indole;(1R*,4R*,4aS*,9bR*)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-1,4-methanopyrido[4,3-b]indole;(1R*,4R*,4aR*,9bS*)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-1,4-methanopyrido[4,3-b]indole;(1R*,4R*,4aR*,9aS*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-4,1-(epiminomethano)carbazole;(1R*,4R*,4aS*,9aR*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-4,1-(epiminomethano)carbazole;(1S*,4R*,4aS*,9aR*)-2,6-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-methano-β-carboline;(1S*,4R*,4aR*,9aS*)-2,6-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-methano-β-carboline;(1S*,4R*,4aS*,9aR*)-6,11-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-(epiminomethano)carbazole;(1S*,4R*,4aR*,9aS*)-6,11-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-(epiminomethano)carbazole;(5aR*,6S*,9R*,10aS*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,9-epiminocyclohepta[b]indole;(5aS*,6S*,9R*,10aR*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,9-epiminocyclohepta[b]indole;(5aR*,6S*,10R*,11aS*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-6,10-epiminocycloocta[b]indole;(5aS*,6S*,10R*,11aR*)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5a,6,7,8,9,10,11,11a-octahydro-5H-6,10-epiminocycloocta[b]indole;(1R*,4S*,4aR*,9aR*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-epiminocarbazole;(1R*,4S*,4aS*,9aS*)-6,10-dimethyl-9-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,9,9a-hexahydro-1H-1,4-epiminocarbazole;(1R*,5S*,5aS*,10bR*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,5-methanoazepino[4,3-b]indole;(1R*,5S*,5aR*,10bS*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,5-methanoazepino[4,3-b]indole;(1R*,4S*,5aS*,10bR*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,4-methanoazepino[4,3-b]indole;(1R*,4S*,5aR*,10bS*)-2,9-dimethyl-6-[2-(6-methylpyridin-3-yl)ethyl]-1,2,3,4,5,5a,6,10b-octahydro-1,4-methanoazepino[4,3-b]indole;(5aR*,6R*,10S*,10aR*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,10-epiminocyclohepta[b]indole;(5aS*,6R*,10S*,10aS*)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-6,10-epiminocyclohepta[b]indole;1′,5-dimethyl-1-[2-(6-methylpyridin-3-yl)ethyl]-1,2-dihydrospiro[indole-3,3′-pyrrolidine];1′,5-dimethyl-1-[2-(6-methylpyridin-3-yl)ethyl]-1,2-dihydrospiro[indole-3,3′-piperidine];2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-ethyl-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-(2-fluoroethyl)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-11-(2,2,2-trifluoroethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;ethyl(7R,10S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate;ethyl(7S,10R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate;11-(4-chlorobenzoyl)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-11-{[4-(trifluoromethyl)phenyl]sulfonyl})-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[2-(2-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-[(Z)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[(E)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[(E)-2-pyridin-3-ylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-(2-pyri din-2-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-[2-(5-ethylpyridin-2-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-(2-pyri din-4-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-(2-pyrimidin-5-ylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[2-(2-methylpyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[2-(6-methylpyridazin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[2-(5-methylpyrazin-2-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(3-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(2-fluorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-[2-(2-chlorophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-bromophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(3-bromophenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-{2-[4-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-{2-[2-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-methoxyphenyl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[(E)-2-phenylvinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-[(E)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[(E)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-[(Z)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[(Z)-2-(4-methylphenyl)vinyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-[(E)-2-(2,4-dimethylphenyl)vinyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[(4-chlorophenyl)acetyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)propyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-(4-isopropenylphenyl)-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-(3-phenylpropyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-fluorophenoxy)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-isoquinolin-7-yl-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-(phenylsulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2,11-dimethyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2,11-dimethyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[(4-fluorophenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[(4-chlorophenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[(4-methoxyphenyl)sulfonyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-{[4-(trifluoromethoxy)phenyl]sulfonyl})-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2,11-dimethyl-5-(pyridin-3-ylsulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-(2-phenylethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-[2-(2-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-[2-(2-methyl-1,4,5,6-tetrahydropyrimidin-5-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-fluoro-11-methyl-5-[2-(4-methylphenyl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-fluoro-5-[2-(4-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-fluoro-5-[2-(3-fluorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2-bromo-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-bromo-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-methoxy-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-2-methoxy-11-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-2-methoxy-11-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)ethyl]-4-methoxy-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethoxy)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-(trifluoromethyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-isopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-[2-(4-chlorophenyl)ethyl]-2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-[2-(4-chlorophenyl)ethyl]-2-isopropyl-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-cyclopropyl-11-methyl-5-[(4-methylphenyl)sulfonyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-cyclopropyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-tert-butyl-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-tert-butyl-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-(4-chlorophenyl)-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-bromo-11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;2-(4-chlorophenyl)-5-[2-(4-chlorophenyl)ethyl]-11-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-[3-(trifluoromethyl)phenyl]-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-pyridin-3-yl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;5-[2-(4-chlorophenyl)ethyl]-11-methyl-2-pyridin-3-yl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;11-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2-(1H-pyrazol-4-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(5aS,7S,10R,10aR)-2,11-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-5,5a,6,7,8,9,10,10a-octahydro-7,10-epiminocyclohepta[b]indole;2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2,12-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;5-[2-(6-chloropyridin-3-yl)ethyl]-2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;2,12-dimethyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2,12-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2,12-dimethyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2-methyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2-methyl-5-[(E)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2-methyl-5-[2-(2-methylphenyl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2-methyl-5-[2-(2-methylphenyl)ethyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-5-[2-(2,5-dimethylphenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-5-[2-(2,5-dimethylphenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-5-[2-(4-chlorophenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-5-[2-(4-chlorophenyl)ethyl]-2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;12-ethyl-2-methyl-5-{2-[3-(trifluoromethyl)phenyl]ethyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7R,11S)-2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;(7S,11R)-2-methyl-5-{(E)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;2-methyl-5-{(Z)-2-[3-(trifluoromethyl)phenyl]vinyl}-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;5-[2-(6-methylpyridin-3-yl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;5-[2-(2-methylphenyl)ethyl]-2-(trifluoromethoxy)-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole;ethyl(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetate;N-(4-chlorophenyl)-2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)acetamide;2-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-N-[4-(trifluoromethoxy)phenyl]acetamide;9-fluoro-6-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-[(2-phenyl-1,3-oxazol-4-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;8-[(6-chloropyridin-3-yl)methyl]-11-fluoro-1,4,5,6,7,8-hexahydro-2H-1,5:3,7-dimethanoazonino[5,4-b]indole;5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;(6R,10S)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;(6S,10R)-5-[2-(6-chloropyridin-3-yl)ethyl]-2,11-dimethyl-5,6,7,8,9,10-hexahydro-6,10-epiminocyclohepta[b]indole;10-methyl-7-[2-(6-methylpyridin-3-yl)ethyl]-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole;10-methyl-7-[2-(2-methylphenyl)ethyl]-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole;7-[2-(4-chlorophenyl)ethyl]-10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole;5-[(4-chlorophenyl)sulfonyl]-8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole;6-isoquinolin-7-yl-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-methyl-6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-methyl-6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-methyl-6-quinazolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(9-methyl-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol;6-(4-methoxyquinazolin-6-yl)-9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-methyl-6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-isoquinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-quinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-quinazolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(4-methoxyquinazolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol;6-(2-methylquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-quinolin-7-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-quinolin-2-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-[4-(4-methylpiperazin-1-yl)phenyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;2-[2-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)ethyl]pyridazin-3(2H)-one;1-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridin-2(1H)-one;9-fluoro-6-[(2-phenylpyrimidin-5-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(1H-benzimidazol-2-ylmethyl)-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-(quinolin-8-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-[(3-methyl-1,2-oxazol-5-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-[(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl]-9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-[(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6′-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,2′-bipyridin-2-one;6-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-ol;7-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinoxalin-2(1H)-one;7-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one;2-[6-(9-fluoro-1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)pyridin-3-yl]pyridazin-3(2H)-one;9-fluoro-6-(2-methylpyrimidin-5-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;9-fluoro-6-(pyridin-3-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-[6-(morpholin-4-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)nicotinamide;6-(1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(quinazolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(isoquinolin-7-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-(isoquinolin-6-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6-[4-(1H-imidazol-1-yl)pyridin-2-yl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;6′-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,2′-bipyridin-2-one;7-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinoxalin-2(1H)-one;7-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-2H-1,4-benzoxazin-3(4H)-one;2-amino-5-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)benzamide;7-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one;(7S,10R)-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-5-(isoquinolin-7-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7S,10R)-11-methyl-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;(7R,10S)-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;7-[(7S,10R)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one;7-[(7R,10S)-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indol-5(6H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one;6-[(6-chloropyridin-3-yl)methyl]-9-fluoro-1,2,3,4,5,6-hexahydro-1,4-methanoazepino[4,3-b]indole;(7R,10S)-11-methyl-5-(quinolin-6-yl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole;and2-[4-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)phenyl]pyridazin-3(2H)-one.
 2. A compound that is6-(1,3,4,5-tetrahydro-6H-2,5-ethanoazepino[4,3-b]indol-6-yl)quinazolin-4-olor a pharmaceutically acceptable salt thereof.